bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating amyloid beta‐induced toxicity in tau‐deficient human neurons
Authors: Ng Bryan , Vowles Jane , Cowley Sally A , Caffrey Tara M , Connor‐Robson Natalie , Wade‐Martins Richard 
Published: December 2020

AbstractBackgroundAmyloid‐b (Ab) and tau aggregates are two major pathological hallmarks and known to be dysregulated in Alzheimer’s disease (AD), leading to widespread aggregation. We now know from tau‐deficient animal models that tau does not merely facilitate Ab‐induced toxicity but is also essential in that particular toxic cascade. However, a tau‐deficient human in vitro model has not been available to corroborate these studies.MethodHere we generated the first MAPT

‐/‐
human induced pluripotent stem cell (iPSC) lines with CRISPR‐Cas9‐mediated genome editing in order to study the effects of tau deficiency in human biological context. We also established a versatile and scalable cortical neuron differentiation protocol which successfully produced a heterogeneous population of functional neurons manifesting cortical identity in co‐culture with rat astrocytes. Furthermore, we extracted brain homogenate from an AD patient to serve as the source of extrinsic Ab in addition to synthetic Ab oligomers.ResultiPSC‐derived MAPT

‐/‐

cortical neurons exhibited lower firing amplitude and frequency compared to MAPT

+/+

neurons at baseline, while expressing similar number of synapses. On the other hand, MAPT

‐/‐

neurons demonstrated impaired axonal outgrowth over 5 days of live imaging. Upon extrinsic AD brain homogenate and/or Ab1‐42 oligomer insults, MAPT

‐/‐

neurons appeared to be protected from axonal degeneration, cytotoxicity and hyperactivation as compared to MAPT

+/+

neurons. However, the MAPT

‐/‐

background was unable to prevent Ab‐induced loss of synapses.ConclusionTaken together, the absence of tau in human neurons resulted in phenotypic changes at baseline and could result in neuroprotection in MAPT

‐/‐

neurons from Ab‐induced toxicity.
Sleep duration genes associated with cognition across the adult age‐range
Authors: Tsapanou Angeliki , Gao Yizhe , Stern Yaakov , Barral Sandra 
Published: December 2020

AbstractBackgroundSleep is implicated in cognitive functioning in young adults, while healthy older adults do not always demonstrate clear associations between sleep and cognitive functioning. Age‐related changes in sleep include a reduction in total sleep time and a greater incidence of sleep disorders, and are also an integral part of neurodegenerations. In the present study, we aimed to: a) identify common genetic variants that may influence self‐reported sleep duration, and b) examine the association between the identified genetic variants and performance in different cognitive domains.MethodA sample of 197 cognitively healthy participants, aged 20‐80 years, were selected from two study cohorts: The Reference Abilities Neural Network and the Cognitive Reserve. Each participant underwent an evaluation of sleep function and assessment of neuropsychological performance on four different domains (memory, speed of processing, fluid reasoning, language), and global cognition. Available imputed genome‐wide genotyped data was used to derive a Polygenic Risk Score (PRS) based on 69 genetic variants previously reported as associated with sleep duration. Multivariate linear models were used to test the associations between the PRS and sleep duration and cognitive performance. Age, sex, and education were used as covariates.ResultHigher PRS was linked to longer sleep duration and then, lower risk of poor performance in global cognition, fluid reasoning, speed of processing, and language, but was not associated with memory.ConclusionWe replicated the association between PRS and longer sleep duration. We additionally found a significant association between the PRS and cognitive function. Our results suggest that common genetic variants influence the link between sleep duration and cognitive health. Sleep duration may represent a potential causal pathway for cognition, and, thus, improving sleep habits might be as useful as a potential therapeutic target to improve cognitive performance. Funding: National Institute of Health (NIH)/ National Institute of Aging (NIA) [Grant numbers: R01 AG026158 and RF1 AG038465], and the Bodossakis foundation.
MALDI‐TOF IP‐MS quantification of plasma amyloid peptides in Alzheimer’s disease
Authors: Lehmann Sylvain , Vialaret Jérôme , Kindermans Jana , Gabelle Audrey , Hirtz Christophe 
Published: December 2020

AbstractBackgroundThe use of biomarkers which reflect Alzheimer’s disease (AD) improved the stratification of patients and the ability to propose personalized care. Their detection using either cerebrospinal fluid analysis (CSF), which is invasive, or using PET imaging, which is costly, is not adapted to large‐scale use. In 2018, Nakamura et al. using MALDI‐TOF IP‐MS generated a new composite biomarker with the amyloid‐ß precursor protein (APP)669–711/Aß42 and Aß40/Aß42 ratios with an AUC above 0.94 to identify subjects with PETAß+. Our primary objective here was to validate the use of this approach to identify AD and predicts its apparence in MCI and pre‐symptomatic patients.MethodThe blood‐based Aß markers were measured with an innovative MALDI‐TOF IP‐MS approach adapted from Nakamura et al., 2018. Briefly, 250 μl of plasma was diluted and spiked with 10 pM of stable‐isotope‐labelled (SIL) Aβ1–38 peptide. Aβ‐related peptides were immunoprecipitated, washed, and eluted with with 70% acetonitrile / 5 mM HCl to a 900‐μm μFocus MALDI plateTM (Hudson Surface Technology) which was pre‐spotted with a mix of α‐cyano‐4‐hydroxycinnamic acid (CHCA) and methanediphosphonic acid (MDPNA). Mass spectra were acquired using a MALDI‐linear TOF mass spectrometer (AXIMA Assurance, Shimadzu/KRATOS) equipped with a 337‐nm nitrogen laser in the positive ion mode. References AD cohorts with CSF biomarkers and longitudinal follow‐up were used.ResultsQuality controls (QC) plasma pools with Low (LQC), Medium (MQC), and High (HQC) (APP)669–711, Aß42 and Aß40 levels were generated to perform the analytical validation. Intra‐day variability were for LQC, MQC and HQC ≈19% for raw MS intensities and ≈6% after internal normalization. Inter‐day variability were ≈16% after normalization. Dilution integrity indicated linear results between 100% and 50% of the initial plasma volume. Three cycles of freeze/thaw test showed a good stability for the 3 target peptides. A cohort of >200 subject’s plasma samples from the memory consultation of the CMRR of Montpellier with Alzheimer’s disease, Mild Cognitive Impairment and other degenerative diseases are being analyzed to demonstrate the clinical interest of this measurement.ConclusionMALDI‐TOF IP‐MS quantification of plasma amyloid peptides reached satisfactory analytical performance for clinical use. Its relevance for Alzheimer disease will be illustrated.
Care trajectories in a cohort of nursing home long‐stay residents with dementia, 2011‐2016
Authors: Xu Dongjuan , Arling Greg , Hass Zach 
Published: December 2020

AbstractBackgroundCare transitions are very common among nursing home (NH) residents with dementia and many of these are deemed inappropriate or avoidable. The study aimed to identify the main care trajectories where NH residents with dementia were receiving care in a cohort from entry to death (or censoring).MethodThis is a retrospective cohort study of Minnesota NH residents with dementia. The study cohort consisted of 2,550 long‐stay residents (≥ 100 days) aged 65 years and older with a diagnosis of dementia who received NH care in Minnesota beginning at 2011. Monthly health care transitions for the cohort was tracked over a 60‐month period.ResultWe found four distinct trajectories among long‐stay NH residents with dementia over the 5‐year period were: 1) residents who died early with high hospitalization and ER visits (n = 967, 37.9%), 2) residents who died later and before death had high hospitalization and ER visits (n = 743, 29.1%), 3) residents who remained in NH (n = 643, 25.2%), and 4) residents who transferred from NH to community (n = 197, 7.7%). Relative to residents who remained in the NH (trajectory 3), residents who died early with high hospitalization and ER visits (trajectory 1) had the severest cognitive impairment, the highest level of depression, and the highest percentages of heart failure, renal failure, cancer, coronary artery disease, and lung disease. Residents who died later (trajectory 2) had the second severest cognitive impairment and the highest percentages of hip fracture and delirium. Residents who transferred to community (trajectory 4) had the best cognitive function and lowest percentages of hip fracture, cancer, lung disease and respiratory failure.ConclusionResidents in the cohort with more severe dementia and multiple comorbidities tended to die either early (trajectory 1) or later in their stays (trajectory 2). In both trajectories, the residents bounced back and forth between nursing facility, ER, and hospital before death. Findings point to the importance of advanced care planning and palliative care for the large percentage NH residents (67% in this study) who are at increased risk of multiple acute care transfers at the end of life.
Patient characteristics and treatment choice in a 65‐84 vs a ≥85 year old population with dementia‐related psychosis: Results from a secondary data claims study
Authors: Ramos Brett A. , Whitford Alex , Brain Cecilia 
Published: December 2020

AbstractBackgroundDementia affects approximately 8 million people in the US and about 2.4 million experience dementia‐related psychosis, i.e. hallucinations and delusions,1‐15 for which there is no approved treatment. Antipsychotics (APs) are routinely used “off‐label” and carry a box warning as they have been shown to increase the mortality risk in dementia16
MethodCriteria for identifying patients with dementia‐related psychosis leveraged the Anonymized Patient Level Data from IBM Truven, a widely utilized claims database, was evaluated for either 2+ ICD 9/10 diagnosis (Dx) OR 2+ prescriptions (Rx) related to Dementia AND Psychosis AND 1+ Dx for Dementia before the first psychosis Dx or Rx. Patients were then excluded based on 2+ Dx on the ICD excluded list (schizophrenia, bipolar, manic). Continuous enrollment criteria were applied in the 2 year washout period and index year within a 5 year study period. The patients were segmented based on age groups and key metrics were investigated to categorize the differences between the two age groups.ResultThe age group of ≥ 85 compared to the 65‐75 group, ran a significantly higher risk of cardiovascular disease, receiving APs, anti‐hypertensives, hypothyroid and diuretic drugs, despite fewer consultations with medical specialists (including psychiatrists); less brain imaging and fewer neurological diagnostics or hospitalizations yet they ran a higher risk of being admitted to inpatient ER, short‐term skilled nursing facilities and being transitioned to Long‐Term Care (LTC).ConclusionThe ≥ 85 age group with dementia‐related psychosis were shown to have a higher comorbid disease burden and, despite an increased mortality risk in this vulnerable population, an even higher off‐label AP use compared to the 65‐75 year old group. Further studies are needed to explore the risks of AP use in this potentially sensitive elderly population of dementia‐related psychosis.
Creating dementia friendly community for social inclusion: A scoping review
Authors: Hung Lillian 
Published: December 2020

AbstractBackgroundSocial exclusion is commonly reported by people with dementia and their families. Dementia‐friendly community has emerged as an idea that holds potential to contribute to the mitigation of social exclusion. The objective of the scoping review is to identify strategies of creating dementia‐friendly communities that support people with dementia and their informal care providers.MethodThis scoping review follows the Joanna Briggs Institute scoping review methodology and takes place between March and May, 2020. The review included studies based in community settings with participants living at home with early to late stages of dementia and their families. It included a three‐step search strategy: (1) to identify keywords from CINAHL & AgeLine; (2) to conduct a second search using all identified keywords and index terms across selected databases (CINAHL, AgeLine, MEDLINE, PsycINFO, Web of Science, ProQuest and Google); and (3) to hand‐search the reference lists of all included articles and reports for additional studies.ResultA total of 28 papers were included in the review. Content analysis identified strategies of creating dementia‐friendly communities: (a) active involvement of people with dementia and carers, (b) inclusive environmental design, (c) public education to reduce stigma and raise awareness, (d) customized strategies informed by dementia‐friendly and inclusive theories.ConclusionThis scoping review provides an overview of current evidence on strategies that support dementia‐friendly communities for social inclusion. The findings offer insights to inform strategies for education, practice, policy and future research.
Longitudinal changes in established and exploratory cerebrospinal fluid biomarkers by PTAU/AΒ42 status in cognitively unimpaired adults
Authors: Van Hulle Carol A , Betthauser Tobey J , Jonaitis Erin M , Batrla Richard , Wild Norbert , Kollmorgen Gwendlyn , Andreasson Ulf , Bendlin Barbara B , Asthana Sanjay , Carlsson Cynthia M , Johnson Sterling C , Zetterberg Henrik , Blennow Kaj 
Published: December 2020

AbstractBackgroundCharacterizing longitudinal changes in AD and neurodegeneration related CSF biomarkers in cognitively unimpaired adults is critical to distinguishing typical aging from disease pathology, Yet longitudinal change in established and especially emerging CSF biomarkers are not well characterized. We examined linear age trends in CSF biomarkers for AD (Ab42, pTau), neurodegeneration (NFL, Neurogranin and α‐Synuclein) and glial activation (YKL40, GFAP, sTREM2, S100B) assayed using the Roche NeuroToolKit (NTK), a panel of automated prototype CSF immunoassays.MethodsAnalyses were based on a subsample of 146 cognitively unimpaired participants who underwent at least two lumbar punctures (total N=402). Cut‐offs for the ratio of pTau/Ab42 were determined using receiver operating characteristic curve analysis in a larger sample of impaired and unimpaired middle‐aged adults (N=167) treating a positive [C‐11]PiB visual rating as the standard of comparison. CSF analytes, plus ratios Ab42/Ab40 and pTau/Ab42, were fit to linear mixed models with random intercepts and slopes. Biomarker status (pTau/Ab42 +/‐) and covariates (gender, APOE4 status, years education) were entered as fixed effects. We also tested for moderation of age effects by biomarker status. P‐values were adjusted for the false discovery rate.ResultsSample characteristics are shown in Table 1. Twenty participants were AD biomarker positive. We observed small but significant subject‐level variation in slopes for most analytes, including the core AD biomarkers, NFL, neurogranin, YKL40, and S100B. Biomarker status (pTau/Ab42) significantly predicted levels of AD related CSF biomarkers (Table 2), but not levels of neurodegeneration or glial activation related analytes. Ab42/Ab40, but not Ab42, levels significantly decreased over time; all other analytes increased over time with the exception of S100B (Figure 1). Changes in biomarker values over time was not moderated by baseline biomarker status for any of the CSF analytes (not shown).ConclusionPrior preliminary analyses (recreated in Figure 2) suggested that baseline values for biomarkers of neurodegeneration and glial activation are not related to core AD biomarkers until later in disease pathology. We have added to those findings, showing that among cognitively unimpaired individuals, significant longitudinal changes in both core AD‐related and emerging CSF biomarkers appear to be independent of early signs of joint amyloid and tau pathology.
A novel inducible complement C3 conditional knockout mouse model: Generation and characterization
Authors: Batista Andre Felipe , Schroeder Maren , Khan Khyrul , Yalcin Esra , Carroll Michael , Lemere Cynthia A 
Published: December 2020

AbstractBackgroundThe classical complement pathway is a complex process involved in the elimination of dead cells, debris, and pathogens, and as well as brain wiring during development. Complement protein C3 is an innate immune molecule central in the complement pathway. It participates in removing pathogens and eliminating synapses, and is elevated with aging and neurodegenerative diseases, including Alzheimer’s Disease. Previously, we showed that lifelong, germline C3‐deficiency protected aged male wild‐type and APPswe/PS1dE9 mice against hippocampal neuronal dysfunction and cognitive decline, despite increasing the Aβ plaque load. However, it remains unknown whether suppressing complement C3 signaling during early stages of AD pathogenesis, when relevant therapeutic interventions might be considered, would confer neuroprotection.MethodTo address this question, we generated the first‐ever C3 floxed (C3fl/fl) mouse line, and then crossed the C3fl/fl mice with an inducible, global Cre line (Rosa26‐Cre‐ERT2+/‐) for 2 generations to generate novel inducible C3 conditional knockout C3fl/fl; Rosa26‐Cre‐ERT2+/‐ mice. Mice aged 2‐3 months received intraperitoneal injections of either corn oil or tamoxifen (75 mg/kg) once a day for 5 consecutive days. We analyzed the C3 serum levels at 7, 14, 30, 60, and 90 days post‐tamoxifen treatment. We also analyzed the mRNA expression of complement C1q and C3 in the brain and liver 60 days following tamoxifen treatment.ResultC3fl/fl;Rosa26‐cre‐ERT2+/‐ mice had a significant 70% reduction in serum C3 levels compared to controls, which was consistent at all timepoints analyzed. We also showed that C3 expression in the liver, the main source of complement proteins, as well as in the brain was reduced, demonstrating effective recombinase activity in these organs. Intriguingly, C1q mRNA expression was increased in the brain and liver following tamoxifen treatment; further studies are underway.ConclusionIn conclusion, we present a novel mouse model in which tamoxifen treatment resulted in sustained lowering of C3 in the serum, liver, and brain. We will next cross this model with AD‐like mouse models of amyloidosis and tau pathology to evaluate whether global C3 lowering in early stages AD pathogenesis is protective and if so, our data would support targeting complement as a therapy for AD.
Driving performance and its correlation with cognitive tests in elderly drivers with cognitive impairments
Authors: Peng Zhouyuan , Kinoshita Ayae 
Published: December 2020

AbstractBackgroundWith the rapid aging of the population, the driving problem of dementia patients has caused increasing concerns among the government, researchers and the public worldwide1. We aim to investigate driving behaviors of elderly drivers with cognitive impairments using a driving simulator. And we are further interested in exploring the correlation between neuropsychological tests and driving performance.MethodsElderly subjects with driving experience who visited the outpatient neurology clinic in the Kyoto university hospital for cognitive complaints from July 2018 to December 2019 were investigated. Cognitive tests were carried out, as well as a questionnaire asking both demographic and driving characteristics. Participants who wished to continue driving were asked to complete the driving tests.ResultsA total of 45 participants were included in the study, ranged in age from 66 to 92 years, of which 57.8% were male. Slightly more than half of participants have returned their driving licenses whereas 20 still hold a valid driving license. Though current drivers had better cognitive functions than retired drivers, poor performance was found on reaction, starting and stopping, signaling, and general. The score of Mini‐mental state examination (MMSE), trail making test (TMT), block design test (BDT) and Alzheimer’s disease assessment scale–cognitive subscale (ADAS‐Cog) were correlated with reaction tests, especially TMT‐B, revealing a slightly higher correlation coefficients for the choice reaction test. MMSE, BDT and ADAS‐Cog had quite high correlation coefficients for sudden braking (ρ1=‐0.806, ρ2=‐0.727, ρ3=0.786, p<0.001). TMT‐B was associated with no signaling (ρ4=0.625, p<0.05) while clock drawing test (CDT) had a correlation with wrong signaling (ρ5=‐0.545, p<0.05). In addition, CDT also showed a negative correlation with going the wrong way (ρ6=‐0.655, p<0.05). MMSE and ADAS‐Cog were moderately correlated with lateral control (ρ7=‐0.620, ρ8=0.560, p<0.05).ConclusionsCurrent elderly drivers had better cognitive functions, but a considerable part of them showed poor performance in the driving tests. Single cognitive tests were shown to have moderate to high correlations with specific driving maneuvers segmented from driving performance. Reference: Kim YJ, An H, Kim B, Park YS, Kim KW. An International Comparative Study on Driving Regulations on People with Dementia. J Alzheimers Dis. 2017;56(3):1007‐1014.
A family‐based genetic study identifies mutations in TLR9 impairing receptor activation: A role for innate immunity in AD pathogenesis
Authors: Cacace Rita , Hoogmartens Julie , Hens Elisabeth , Buist Arjan , Cras Patrick , Sieben Anne , Vandenberghe Rik , Engelborghs Sebastiaan , De Deyn Peter Paul , Martin Jean‐Jacques , Moechars Diederik , Van Broeckhoven Christine ,   BELNEU Consortium
Published: December 2020

AbstractBackgroundFamily‐based genetic studies in early‐onset Alzheimer disease (EOAD), prompting early gene discoveries, remain powerful for the identification of novel genes in AD. Causal mutations in APP, PSEN1 and PSEN2 explained <10% of EOAD patients, while several EOAD families remained genetically unexplained. We identified a multigenerational Flanders‐Belgian family with autosomal dominant EOAD. DNA, biomaterials and clinical data from two consecutive informative generations were available: 5 AD patients (onset 64.2±13.2 years, range 52‐85) of which 2 with a definite neuropathological diagnosis and 9 unaffected/at‐risk individuals.MethodWhole exome sequencing of 4 patients. Selection of shared rare non‐synonymous variants, validation of co‐segregation with disease and variants frequency assessment using massive parallel‐targeted sequencings (MPS). We used genotyping of STR markers to define haplotypes. Coding regions of candidate genes were sequenced using MPS in a Belgian cohort of 320 EOAD (onset 57.8±5.9y, range 33‐65) and 1166 late‐onset (LO)AD (onset 77.1±6.5y, range 66‐96) patients and a control cohort of 934 persons (inclusion 70.45±9.2y, range 52‐100). Variants pathogenicity was predicted using CADD scores cutoff>20. Evaluation of functional effects by NF‐κB luciferase assay.ResultThree rare variants co‐segregated with AD in the family: CCR3 p.F249Hfs*23 (rs561062190), ZNF589 p.T355M (rs376706270) and TLR9 p.E317D (novel) and are located within a co‐segregating haplotype block of 15.3 cM at ch3p21. Only the TLR9 variant was absent in controls. TLR9 is a DNA‐sensing receptor expressed in immune cells, recognizes unmethylated CpG oligonucleodides and is responsible for innate immune cells activation and mounting acquired responses. The NF‐κB luciferase assay showed that p.E317D, located within the ligand sensor pocket of TLR9, caused a 50% reduction in receptor activation. TLR9 resequencing identified additional rare variants carriers: 7 in EOAD (7/320, 2.19%) and 19 in LOAD (19/1166, 1.63%) patients and 8 in controls (8/934, 0.86%), while TLR9 p.E317D was absent. Of the rare variants, 16 were in patient‐only, 3 in patients and controls and 5 in controls‐only. The NF‐κB luciferase assay indicated reduced TLR9 activation for the novel variants specific to EOAD patients and with a CADD score >20.ConclusionWe discovered TLR9 as candidate gene in AD with a mechanism of loss of receptor activation.