bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age disparities in depression and subjective cognitive decline among a U.S. population‐based sample
Authors: Brown Monique J 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD), a risk factor for Alzheimer’s disease (AD), has been theorized as one of the first signs of preclinical AD. Depression has been shown to be a risk factor for SCD among older populations. However, studies examining the age disparities in this association among US population‐based samples are lacking. Therefore, the aim of this study was to examine the potential age disparities in the association between depression and SCD.MethodsData for this cross‐sectional study were obtained from the 2018 Behavioral Risk Factor Surveillance System Survey, a nationally representative sample of the US non‐institutionalized population. Individuals answering questions on depression and SCD were included (n=2,742). SCD was operationalized by the question: “During the past 12 months, have you experienced confusion or memory loss that is happening more often or is getting worse?” Multivariable logistic regression models adjusting for gender, race/ethnicity, income, and education were used to determine the associations between depression and SCD by age group (middle aged, aged 45‐59 (n=1,076); “young old”, aged 60‐69 (n=880); “middle old”, aged 70‐79 (n=585); and older, aged 80 and older (n=201).ResultAfter adjusting for gender, race/ethnicity, income, and education, those who were aged 45‐59 and reported depression were six times as likely (adjusted OR: 5.89; 95% CI: 3.55 – 9.79) to have SCD. Among individuals aged 60‐69, those who reported depression were four times as likely (adjusted OR: 3.52; 95% CI: 2.06 – 6.01) to have SCD within the past year. Among individuals aged 70‐79, those who reported depression were three times as likely (adjusted OR: 3.11; 95% CI: 1.64 – 5.89) to have SCD within the past year. Among individuals aged 80 and older, those who reported depression were twice as likely (adjusted OR: 2.45; 95% CI: 0.89 – 6.78) to have SCD within the past year.ConclusionDepression was associated with SCD among all age groups. However, as age decreased, the strength of the association increased. These findings suggest that SCD interventions addressing depression may be warranted for middle‐aged and older adults. Future research should assess potential pathways between depression and SCD among middle‐aged and older populations.
The ‘fold line’ shaped relationship between age, years of schooling and the Mini‐Mental State Examination scores in the aged 40 years or above: A cross‐sectional study in a rural area of Xi’an, China
Authors: Shang Suhang , Wang Jingyi , Zhang Binyan , Wang Jin , Jiang Yu , Chen Chen , Dang Liangjun , Qu Qiumin 
Published: December 2020

AbstractBackgroundMMSE is commonly used to assess cognitive function.MethodParticipants were recruited from a village. The relationship between age, years of schooling (YOF) and MMSE scores was analyzed by multivariate linear regression and stratified analysis.Result1799 subjects were enrolled in the study, 1613 subjects aged 40‐69 years, and 186 subjects aged ≥70 years. 222 subjects were illiterate, 568 subjects received 1‐6 YOF, and 1009 subjects received ≥ 7 YOF. After the confounding factors were corrected, MMSE score decreased by 0.093 points (β=‐0.093, P<0.001) for every 1 year of age increasing in the subjects aged 40‐69 years, while that was 0.302 points (β=‐0. 302, P=0.001) in the subjects aged ≥70 years; and increased by 0.863 points (β=0.863, P<0.001) for each additional YOF in the subjects with 0‐6 YOF, while that was 0.179 points (β=0.179, P<0.001) in the subjects with ≥7 YOF. MMSE score expectation equation was established in four subgroups: (1) aged 40‐69 years and 0‐6 YOF: MMSE = 21.282 + 0.198 × gender (female: 0; male: 1) + 0.004 × age (value 40‐69) + 0.787 × YOF (value 0‐6); (2) aged 40‐69 years and ≥ 7 YOF: MMSE = 29.720 + 0.100 × gender (female: 0; male: 1) ‐ 0.078 × age (value 40‐69) + 0.195 × YOF (value 7‐15) (3) aged ≥ 70 years and 0‐6 YOF: MMSE = 39.227 + 1.461 × gender (female: 0; male: 1) ‐ 0.294 × age (value 70‐85) + 0.889 × YOF (value 0‐6); (4) aged≥ 70 years and ≥ 7 YOF: MMSE = 48.000 + 1.651 × gender (female: 0; male: 1) ‐ 0.308 × age (value 70‐85) ‐0.048 × YOF (values 7‐15).ConclusionIn the population aged 40 or above in rural areas of Xi'an, China, with the increase of age, the rate of decline of MMSE score is higher in people aged ≥70 years than that in those aged 40‐69 years; as the increasing of years of schooling, the growth rate of MMSE scores is higher in people with 0‐6 years of schooling than that in people with ≥7 years of schooling.
Heterogeneity of Alzheimer’s disease: Insight from a novel mouse model of amyloid and tau lesions based on the inoculation of human brain preparations
Authors: Lam Suzanne , Boluda Susana , Herard Anne‐Sophie , Petit Fanny , Duyckaerts Charles , Delatour Benoit , Haïk Stéphane , Dhenain Marc 
Published: December 2020

AbstractBackgroundA major challenge in clinical research is to better understand the heterogeneity of AD. Indeed, AD is heterogeneous regarding its origin, neuropathology and clinical expressions. While classical sporadic forms of AD (clAD) evolve over approximately 10 years, the “rapidly progressive form of AD” (rAD) is a non‐genetic aggressive form associated with a rapid clinical decline that evolves over approximately 2 years (Schmidt et al., Arch Neurol. 2011). Several studies have shown that the experimental inoculation of brain samples with Aβ‐ and/or tau pathology into transgenic (tg) mouse models overexpressing mutant human APP or tau promotes either Aβ or tau aggregation in the brain of the recipient animal (Gary et al., Acta Neuropathol Com. 2019). The phenotype of the inoculated brains is moreover reproduced in the recipient host (Watts et al., PNAS. 2014). The aim of this work was to study the impact of the inoculations of rAD versus clAD‐human brain preparations in tg mice mouse models of β‐amyloidosis to explore the mechanisms associated to AD heterogeneity.MethodBrain samples were characterized pathologically and biochemically. The rAD, clAD, and ctrl (non‐Alzheimer) samples were inoculated in the CA1 region of 2‐month‐old APP/PS1dE9 mice (n = 15‐20/group). At 8 months post‐inoculation, an object recognition task (V‐maze) was conducted to assess memory performance. Aβ deposits (4G8 antibody), tau inclusions (AT8 antibody) and synaptic density were then quantified by immunohistochemistry in the hippocampus.ResultMice inoculated with either rAD or clAD brain preparations developed a similar increase of Aβ plaques and tau deposits as compared to ctrl‐inoculated mice. However, only the aggressive form of AD (rAD) led to significant cognitive alterations (Figure 1) and synaptic loss (Figure 2) after 8 months.ConclusionAPP/PS1dE9 mice inoculated with AD brain preparations are new models to study both amyloid and tau lesions occurrence. Our results suggest that, independently from the amyloid plaque load or the severity of tau intraneuronal pathology, synaptic health variability may contribute to the heterogeneity of AD‐like phenotype. Acknowledgment: We thank France‐Alzheimer and the NeuroCEB/CNR‐prion brain banks.
An integrated epigenetic‐genetic study of neuropathology in the Brains for Dementia Research cohort
Authors: Hannon Eilis , Shireby Gemma , Brookes Keeley J. , Neilson Grant , Dahir Aisha , Walker Emma , Lunnon Katie , Love Seth , Thomas Alan J. , Morgan Kevin , Francis Paul T. , Mill Jonathan 
Published: December 2020

AbstractBackgroundIn addition to the APOE locus, there has been considerable success in identifying genetic variants associated with an increased risk of developing Alzheimer’s disease (AD). However, there remains considerable uncertainty about the causal genes involved in AD neuropathology and the way in which these loci are functionally regulated by AD risk variants. As the majority of genetic variants are hypothesised to act via disruptions to gene regulation, there is increasing interest in the role of the epigenome, which encompasses a diverse number of chemical modifications to DNA and nucleosomal histone proteins that directly influence gene expression.MethodsWe have profiled DNA methylation in 1,284 brain samples from up to two regions (prefrontal cortex and occipital cortex) from 656 individuals in the Brains for Dementia Research (BDR) cohort. After stringent quality control, we performed epigenome‐wide association studies of four quantitative measures of neuropathology, Braak stage, Thal amyloid stage, Lewy Body stage and Cerad stage. Using matched genetic data available for these samples, performed a genome‐wide association study of methylomic variation to identify DNAm quantitative trait loci (mQTLs). These mQTL were then were integrated with results from AD GWAS, using summary data‐based Mendelian randomisation, to identify loci where DNA methylation is associated with AD. Finally, we generated polygenic risk scores for these samples and performed an epigenome‐wide study of genetic risk for AD.ResultsWe identified multiple differentially methylated positions (DMPs) associated with neuropathology and AD polygenic risk score, replicating previous findings at known loci and implicating genes linked to known neuropathological pathways. Integrating our database of mQTLs with summary data from a recent AD GWAS, we report pleiotropic associations between AD and DNA methylation at several sites in the genome, including associations annotated to genes implicated in AD (e.g. SLC39A13, SPI1, MS4A6A, and BCL3).ConclusionsWe identified epigenetic differences associated with detailed measures of neuropathology providing insights on the molecular processes that underlie the disease progression. Furthermore, we characterised the complex relationship between genetic and epigenetic variation, identifying molecular consequences of high genetic risk for AD and prioritising candidate genes for functional follow up.
Alzheimer's polygenic risk score in general population reveals new biomarkers for early diagnosis
Authors: Karkar Slim , Philippe Cathy , Hager Alexa , Mangin Jean‐Francois , Frouin Vincent 
Published: December 2020

AbstractBackgroundIn aging population, Alzheimer's disease (AD) with its different stages (preclinical, prodromal, mild to severe) has a strong genetic component. For a given individual and using summary statistics available from powerful reference GWAS in Alzheimer’s disease (IGAP, Lambert, 2013), one can compute a Polygenic Risk Score (PRS) for AD, that is a cumulative genetic risk computed with one subject’s genome variants. Using individual's PRS and MRI images in an aging general population like UK Biobank, we could point at imaging markers (endophenotypes) associated with early stages of AD.Method16,549 subjects aged 47‐74 from UK Biobank were included in the analysis. Using anatomical T1 MRI images (3T), opening measurements in 123 sulci were extracted with BrainVisa/Morphologist pipeline. Individual's PRS were computed using PRSice and summary statistics from IGAP study and then have been tested for an association with sulcal opening measurements.ResultWe obtained 24 sulci for which opening measurements was either positively or negatively associated with PRS (p < 0.05 after FDR correction). 17 sulcal opening showed increased widening w.r.t PRS with a main focus around the precuneus region, with superior parietal and central sulci. 7 sulcal opening showed opposite effect w.r.t the PRS and are located mostly in the orbital and insula region. See Figure for details.ConclusionFor neurological disease like AD that have a strong genetic background, the combination of genetics and imaging data in large, aging general population studies like UK Biobank, provides powerful tools to identify new possible early markers of neurodegeneration. Focus on early risk patterns as the ones presented here with a main result on parietal sulcal alterations might facilitate identification of individuals at risk for cognitive decline and possibly support diagnostic procedures for AD.
Predictors of antipsychotic usage among patients with dementias and mild cognitive impairment
Authors: Dhikav Vikas 
Published: December 2020

AbstractBackgroundAntipsychotics are commonly used to control a variety of psychotic symptoms e.g. agitation, or aggression and wandering behaviors which are part of behavioral and psychological symptoms of dementia (BPSD) in various dementias and mild cognitive impairment (MCI). Despite their extensive usage in these patients, predictors of their usage are unknown.MethodA total of 948 patients with memory/cognitive complaints from July 2012 to December 2015 were screened in the present study. Those who met the diagnosis of MCI [Clinical Dementia Rating (score=0.5)] or Diagnostic and Statistical Manual‐IV (DSM‐IV) for diagnosis of dementia were recruited for the present study if they had BPSD and were on antipsychotic drugs. Fazekas White Matter Lesion (WMLs) Score was used to study the WMLs leasion load. BEHAVE‐AD scale was used to rate the severity of cases.ResultWe found a total of 398 patients with dementias and [M:F=330:68] and 550 patients with MCI with the mean age 74±4.1 and duration of illnesses 3.1±1.2 years were studied. In the MCI group [348: 198], the mean age was 64±3.1 and duration of illnesses 2.1±1.2 years. Antipsychotics were most likely used by those with vascular dementia, mixed dementias, AD with white matter lesions, dementia with co morbidities; and those with advanced illness. Patients older than 85 years were more likely to be on antipsychotics. Adverse effects of antipsychotics in elderly with dementias were common.ConclusionCertain categories of patients in dementia/MCI groups are more likely to receive antipsychotics than other patients.
Isolation of bioactive components from Corallocarpus epigaeus tuber and inhibitory potential against various molecular forms of acetylcholinesterase
Authors: Loganathan Chitra , Sakayanathan Penislusshiyan , Thayumanavan Palvannan 
Published: December 2020

AbstractBackgroundIn human, acetylcholinesterase (AChE) is involved in cholinergic neurotransmission. AChE exhibits as different globular form such as G4 (tetramer), G2 (dimer) and G1 (monomer). For the most part of the adult brain G4 forms is present. Nevertheless, under dementia such as Alzheimer’s disease (AD) conditions, the ratio between G1 and G4 form is increased which is involved in disease progression. Inhibition of AChE is considered important therapeutic intervention to overcome the AD. Corallocarpus epigaeus comes under the family of Cucurbitacea has known for the biological properties such as anti‐snake venom, analgesic, anthelminthic properties and antidiabetic activity. Identifying natural compounds with AChE inhibition is considered important for AD treatment. In the present study, bioactive fraction extracted from tuber of C. epigaeus was investigated for its inhibition against different molecular forms of AChE in in vitro.MethodDried tuber powder of C. epigaeus was extracted using various solvents sequentially by increasing polarity in Soxhlet apparatus. Methanol extract was further purified by silica column chromatography. The partially purified fraction was studied for the inhibition against different molecular forms of AChE. Kinetic analysis was carried out to determine the type of inhibition and inhibitor constant. The active compounds in partially purified fraction were determined using gas chromatography mass spectrum analysis (GCMS).ResultPartially purified fraction of methanolic extract of C. epigaeus tuber inhibited all the molecular forms (G1, G2 and G4) of AChE at microgram per milliliter concentration. Kinetic analysis revealed the mixed type non‐competitive mode of inhibition with low Ki value. GCMS analysis 4H‐pyran‐4‐one, 2,3‐dihydro‐3,5‐dihydroxy‐6‐methyl and alpha‐linolenic acid as major constituents in the extract.ConclusionThe bioactive components in tuber of C. epigaeus inhibited AChE in in vitro. This is the first report on the inhibitory effect of C. epigaeus tuber extract against AChE. Further in vivo studies are necessary to understand the anti‐dementia effect of C. epigaeus.
CAIDE risk score for the prediction of dementia risk in Mexican elders: 10/66 Dementia Research Group, population‐based study in Mexico
Authors: Salinas‐Contreras Rosa Maria , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa 
Published: December 2020

AbstractBackgroundCAIDE (Cardiovascular Risk Factors, Aging, and dementia) Dementia Risk Score was developed to identify subjects with risk for developing dementia; using cardiovascular risk factors for dementia. CAIDE has showed to have a good predictive value. Mexican elders have different risk factors for dementia; the use of this type of score could be a good alternative to detect subjects at risk and implementing prevention strategies.MethodWe include 1,111 subjects of >65 years of age, without cognitive impairment and who had the information complete to calculate CAIDE [age (< 47, 47‐53, >53 years old), gender, education (> 10 years, 7‐9 years, < 7 years), systolic blood pressure (<140 or >140mmHg), body mass index (<30 or >30 kg/m2), the auto‐report of dyslipidaemia (the original CAIDE use only hypercholesterolemia) and physical activity. Diagnosis of dementia after the follow‐up was according to 10/66 algorithms, we determinate the predictive properties of CAIDE score.ResultThose with a CAIDE score of 6‐7 showed a sensitivity of 66.23%, specificity of 34.7% and the 37.63% of proper classification at three years of follow‐up; for those with score of 8‐9, had a sensitivity 24.68%, specificity of 73.69% and the 69.18%, and for those with a score 10‐11, shown a sensitivity of 5.19%, specificity of 93.5% and the 85.4% of proper classification.ConclusionCAIDE score show a good specificity and sensibility. CAIDE scores of 6‐7 showed the best sensitivity but the 8‐9 scores obtain the best specificity. But we should consider different things for example we population have > 65 years old, this conditioning all our sample to obtain 4 points, and we use self‐report for some measures. CAIDE does not include diabetes, which has demonstrated to be an important risk factor for dementia in our population.
Proteogenomic analysis of cerebrospinal fluid reveals causal role of proteins from the autophagy‐lysosome pathway in Parkinson’s disease
Authors: Yang Chengran , Farias Fabiana H.G. , Harari Oscar , Rhinn Herve , Cruchaga Carlos , Benitez Bruno A. 
Published: December 2020

AbstractBackgroundIntegrating genetic variants associated with protein levels (protein quantitative trait loci; pQTLs) with variants from genome‐wide association studies (GWAS) using Mendelian randomization approaches has uncovered a causal role of previously unsuspected proteins in several diseases. We have successfully applied a combination of targeted proteomic and genomic approaches to the cerebrospinal fluid (CSF) of Alzheimer Disease (AD) patients to identify multiple novel genetic associations. However, there are currently no proteogenomic studies in Parkinson’s Disease (PD).MethodsWe used the SOMAscan 1.3k Assay (∼1,305 SOMAmers) in ∼1015 samples from the ADRC‐WUSTL. SOMAscan data from the Parkinson's Progression Markers Initiative cohort and Sasayama D, et al 2017 were used as replication cohorts. After stringent QC steps were applied to SOMA data, each SOMAmer was log10 transformed and standardized to zero. We used linear additive genetic regression models adjusted for age, sex, genotyping array and the first two principal components using Plink 1.9. We used the R package MendelianRandomization to integrate our CSF pQTL variants with PD‐related SNPs from the 2019 METAPD GWAS.ResultsWe found significant cis‐pQTLs for Cathepsin B (p = 3.6 × 10−27), Alpha‐L‐iduronidase (p = 3.4 × 10−41) and Galactin‐3 (p = 2.7 × 10−41). MR found significant causal associations of PD risk with pQTLs for IDUA (b = 1.2, p = 5.0 × 10−6), CSTB (b = ‐1.4, p = 2.7 × 10−4) and Galactin‐3 (b = ‐1, p = 4.0 × 10−2). Most importantly, we found an association with progranulin (PGRN) trans‐pQTLs (p = 2.5 × 10−9). This association was replicated in the PPMI cohort (p = 1.9 × 10−9), and MR confirmed the significant causal link of PGRN (b = 4.6, p = 1.0 × 10−4) with PD. The PGRN pQTL in CSF is located in the LRRK2 gene locus. This SNP is also associated with the CSF levels of proteins from two additional PD‐associated genes CTSB (p = 1.6 × 10−3) and glycoprotein nmb (GPNMB, p = 1.5 × 10−4).ConclusionOur proteogenomic approach identified LRRK2 as a genetic modifier of three additional PD‐associated proteins in CSF. MR analyses confirmed the causal link of proteins from the autophagy‐lysosome pathway with PD. Our data provide new biological insights into how LRRK2 modifies PD risk and novel markers for screening of LRRK2 kinase activity.
Identifying gene expression signatures in individuals with minimal cognitive impairment in the presence of advanced Alzheimer's disease pathology
Authors: Gaur Pallavi , De Jager Philip L. , Menon Vilas 
Published: December 2020

AbstractBackgroundThe pathological hallmarks of Alzheimer’s disease such as amyloid plaques and neurofibrillary tau tangles are usually associated with the primary clinical manifestation of cognitive decline. Recent studies implicate that a subset of “resistant” individuals have high burden of AD pathology, yet do not exhibit dementia (cognitive decline). Here, we compared the publicly available gene expression profiles of these resilient individuals and susceptible individuals (showing both AD pathology and cognitive decline) in dorsolateral prefrontal cortex (DLPFC) brain tissue obtained from individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP).MethodWe conducted bulk RNA‐Seq analysis on data from the DLPFC of 239 individuals with differing AD pathological findings and clinical consensus diagnosis. This data set is available through the Synapse portal (AMP‐AD consortium). The patients were subdivided into four groups of control, weakly resilient, strongly resilient, and susceptible, according to their degree of pathology (Braak stage) and clinical cognitive diagnosis. The control group included individuals with no cognitive impairment and initial braak stages; 0 and 1. The weakly and strongly resilient groups included individuals with no and mild cognitive impairment with advanced Braak stages respectively, while the susceptible group comprised individuals with AD‐dementia and advanced tauopathy (Braak stage>4). We used DESeq2 between these groups with a multiple factor approach that corrected for sex and age of death.ResultOur findings provide insight into genes that may be attributable to weak or strong resilience in the presence of relatively advanced AD pathology. Some of these candidate genes, such as SERPINA5 and GIPR, have previously been associated AD pathology and other neurodegenerative diseases, but we also identified a set of less well‐characterized genes that may be involved in cognition specific contributions to AD resilience.ConclusionOur study recapitulates genes with known associations with AD pathology, and also identifies new candidate genes and pathways worth pursuing further as potential therapeutic targets to mitigate cognitive decline associated with AD. As ongoing proteomics and snRNA‐seq data is generated, these candidates may be further refined through an integrative approach, yielding new insights into pathways involved in AD pathology‐mediated decline and cognitive resilience.