bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of family carers of people with Down syndrome suffering from Alzheimer’s disease
Authors: Rebillat Anne‐Sophie , Hiance‐Delahaye Anne 
Published: December 2020

AbstractBackgroundCaring for people with dementia is highly challenging, and family carers are recognised as being at increased risk of physical and mental ill health. (Pinquart & Sorensen, 2007). People with Down syndrome (DS) face an extremely high risk to develop dementia due to Alzheimer’s disease (AD) (Ballard C et al., 2016). Risk for AD increased from 23% in those aged 50 years to 80% in those aged 65 years and above (McCarron et al, 2017). The management of these patients is particularly complex given the pre‐existing intellectual disability, behaviour and co‐morbidities (Esbensen AJ et al, 2018). Behavioural and psychological symptoms were found to be a major cause for referral (Adams et al, 2008) and caregivers reported difficulty to understand behavioural changes (Iacono T et al., 2014). Caregivers were showed to have misconceptions about AD development in DS and underutilize available resources (Ilacqua et al, 2019) but there is no data concerning family carers in particular.MethodThe aim of this study is to describe family carers of people with DS and AD followed at Lejeune Institute in Paris. Data were collected retrospectively and included family carers of patients with DS and suffering from AD followed at Lejeune Institute in Paris (France) from November 2016 to December 2019.ResultAbout 600 patients with DS and aged at least 35 years have had geriatric assessments in our clinic. Around a third have developed AD. A large part of them lived in institutions but with the support of family carers who face the challenge of pathological aging.ConclusionIt is crucial to take interest in these family caregivers because of the complexity and the burden of diagnosis of AD in DS, which institutional care does not necessarily reduce.
Southern European genetic ancestry shows reduced APOE E4 risk for Alzheimer disease in Caribbean Hispanic population
Authors: Rajabli Farid , Adams Larry D. , Tejada Sergio , Rodriguez Vanessa C. , Mena Pedro Ramon , Prough Michael , Bussies Parker , Feliciano Nereida I. , Silva‐Vergara Concepcion , Contreras Maricarmen , Hamilton‐Nelson Kara L. , Acosta Heriberto , Vance Jeffery M. , Cuccaro Michael L. , Feliciano‐Astacio Briseida E. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: December 2020

AbstractBackgroundThe APOE ε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among non‐Hispanic White (NHW) populations APOE shows the strongest effect in Northern European (NEu) (rs429358: OR = 3.32, CI:3.20‐3.45) and has a relatively lower effect in Southern European (SEu; i.e., Iberia, Italy, etc) populations (rs429358: OR = 2.27, CI:2.06–2.50). However, it is not clear if this difference in effect is due to genetic or environmental effects. Hispanic/Latino populations with a large proportion of SEu ancestry provide a unique opportunity to assess both global SEu ancestry (i.e., genome‐wide ancestry) and local SEu ancestry (chromosome/region specific ancestry) in populations with environments distinct from SEu. Our objective is to use data from a Caribbean Hispanic Puerto Rican (CHIPR) population to assess the role of SEu genetic ancestry and the APOE gene on Alzheimer disease (AD) risk.Method
APOE and genome‐wide genotyping were performed in 412 CHIPR (231 cases, 181 controls). Local ancestry was calculated using SHAPEIT and RFMix. Global ancestry was assessed using GENESIS. Association between affection status and APOE genotype was analyzed using logistic regression models by adjusting for age, gender, and population substructure.ResultThe admixture analysis showed that CHIPR have a substantial SEu ancestral component (∼67%). At the APOE gene, the local ancestry was 68% SEu, 20% African, and 12% Amerindian. Logistic regression model showed a significant association of the APOE ε4 risk allele with AD (CHIPR: OR = 1.9 CI:1.3‐2.8, p‐value = 4.4e‐4).ConclusionWe found that the effect of the APOE ε4 risk allele in CHIPR with the high SEu ancestral background (∼67%) is similar to the effect observed in Southern European populations, despite having a distinct environment. Our results support the hypothesis that SEu genetic ancestry modulates the risk of APOE in CHIPRs. This suggests that subcontinental ancestry could also play an important role in modulating the risk for other known AD candidate. Studying the sub‐continental (NEu and SEu) ethnic disparity in the genetics of AD, provides critical information to advance the development of novel therapeutic measures.
LRP1 mediates tau endocytosis in a process that is modulated by apolipoprotein E
Authors: Cooper Joanna M. , Migliorini Mary , Arai Allison L. , Muratoglu Selen C. , Hyman Bradley T. , Strickland Dudley K. 
Published: December 2020

AbstractBackgroundCognitive decline in Alzheimer’s disease correlates with the spreading of neurofibrillary tangles consisting of aggregated forms of tau from the entorhinal cortex to synaptically connected brain regions. It is unclear how tau aggregation propagates across the brain but may involve trans‐synaptic transfer of tau between neurons or uptake of extracellular tau that is constitutively secreted from neurons. Specific receptors involved in these processes have remained elusive, and here we investigate the hypothesis that the LDL receptor‐related protein 1 (LRP1) functions as an endocytic receptor for tau.MethodWe employed 125I‐labeled tau to quantify its cellular uptake, confocal microscopy to examine its colocalization with LRP1, and surface plasmon resonance to assess direct binding of tau and phosphorylated forms of tau to LRP1.ResultOur results reveal that monomeric tau binds LRP1 with high affinity, while curiously, phosphorylated forms of tau bind LRP1 with much lower affinity. The studies confirm that LRP1 internalization is attenuated the LRP1 antagonist RAP and is reduced by 70% in LRP1‐deficient cells. Confocal microscopy reveals that internalized tau colocalizes with LRP1 in endocytic vesicles. Most of the LRP1‐mediated uptake of tau leads to its lysosomal degradation. We also demonstrate that apolipoprotein E (ApoE) inhibits LRP1‐mediated tau internalization, with the ApoE4 isoform being a more potent inhibitor than other ApoE isoforms. Our studies in LRP1‐deficient cell lines confirm that a RAP‐insensitive second internalization mechanism occurs for tau, suggesting the existence of an LRP1‐independent receptor‐mediated process for tau uptake.ConclusionLRP1 functions as an endocytic receptor for tau, mediating the uptake of monomeric forms of tau resulting in its degradation. The ability of ApoE4 to modulate LRP1‐mediated uptake of tau may disrupt the normal physiological process of tau catabolism, leading to tau uptake by other mechanisms causing the spreading of neurofibrillary tangles and exacerbating the progression of tau‐mediated cognitive loss.
Serum neurofilament light and whole brain volume associate with machine‐learning derived brain‐predicted age in the British 1946 birth cohort
Authors: Wagen Aaron , Coath William , Keuss Sarah E , Buchanan Sarah M , Storey Mathew , Lu Kirsty , Pavisic Ivanna M , James Sarah‐Naomi , Street Rebecca E , Parker Thomas D , Lane Christopher A , Keshavan Ashvini , Murray‐Smith Heidi , Cash David M , Malone Ian B , Wong Andrew , Henley Susie , Crutch Sebastian J , Wellington Henrietta , Heslegrave Amanda J , Zetterberg Henrik , Fox Nick C , Richards Marcus , Cole James , Schott Jonathan M 
Published: December 2020

AbstractBackgroundAge is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides a unique opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained on a large sample of healthy brains (N=2001). Brain age has previously been related to cognitive ageing, physiological ageing and mortality risk (DOI: 10.1038/mp.2017.62), supporting the validity of this approach for assessing biological ageing.Method502 participants in the Insight 46 study, all born during one week in 1946, completed baseline cognitive and neuroimaging assessments at age 69‐71. 468 underwent combined 18florbetapir PET‐MRI scans, from which amyloid status (positive/negative), whole brain volume (WBV), total intracranial volume (TIV) and hippocampal volumes (HV) were derived. The T1‐weighted sequence was passed through the Brain‐age algorithm (https://github.com/james‐cole/brainageR), deriving brain predicted‐age (BPA) and brain‐predicted age difference (brain‐PAD; BPA minus chronological age). Serum neurofilament light (NFL) concentration was measured via Simoa immunoassay. A Preclinical Alzheimer’s Cognitive Composite Score (PACC) was calculated as a mean of z‐scores of the Mini‐mental state exam (MMSE), logical memory delayed recall, digit symbol substitution score and the Face‐Name test. Life course metrics (childhood cognitive scores, education level and Framingham Risk scores) were obtained from previous cohort assessments. Multivariate regression models were used to investigate whether life course metrics predict BPA, as well as whether NFL levels, brain volumes, or cognitive scores correlated with BPA, adjusting for chronological age.ResultThere was a significant difference between the 229 females assessed (mean BPA 65.2 years) compared with the 239 males assessed (mean BPA 70.7). BPA was independently associated with serum NFL concentration (p = 0.071) and inversely with whole brain volume (p < 0.001). Life course factors did not predict brain age.ConclusionThe results showed a significant association of BPA, a cross‐sectional imaging metric, with a biochemical marker of neuronal damage (NFL) and sex. BPA has utility as an imaging metric that can integrate multiple modalities contributing to biological age, with potential as a predictive biomarker of cognitive decline.
Deep phenotyping of the 5XFAD model: IU/JAX/PITT MODEL‐AD center
Authors: Oblak Adrian L. , Carter Gregory W. , Howell Gareth , Rizzo Stacey J. Sukoff , Sasner Michael , Territo Paul R. , Ash Carl T. , Ingraham Cynthia , Kotredes Kevin P. , Bleckert Adam , Masek Marissa , Patel Neil , Chidambaram Ritesh , Ragan Tim , Lamb Bruce T. ,   MODEL‐AD
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia without an effective treatment. Animal models of AD have been valuable tools to understand familial or early onset AD, but to date have not been predictive for translational research. The Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center is developing, validating, and distributing novel mouse models of late‐onset AD (LOAD) that can be used to develop novel therapeutics. Using the 5XFAD model of early onset AD, we have established pipelines to characterize models across multiple sites using biochemistry, histology, functional assays, in vivo MRI and PET imaging, and Serial Two‐Photon (STP) tomography whole brain imaging.MethodsAt designated time points, animals were subjected to the following assays: Functional ‐ behavioral testing paradigms, and in vivo MRI and PET scanning followed by secondary validation with autoradiography. Biochemistry/Histology ‐ mice were sacrificed, perfused, and tissue harvested, with half of the brain frozen and the other half fixed. On frozen tissue samples we performed bulk RNA‐seq. On fixed tissue samples, we assessed AD relevant changes using the following stains and antibodies: X34 (plaques and NFTs), Lamp1 (dystrophic neurites), Iba1 (microglia). STP Whole Brain Imaging ‐ on additional fixed tissue samples we performed whole brain imaging and regional analysis of Methoxy‐X04 labeled plaques using the TissueCyte® imaging platform.ResultsCombined assessment of the 5XFAD model revealed systematic neurodegenerative changes in the mouse brain. Multiple data sets including histology, biochemistry, RNA‐seq, transcriptomics, in vivo imaging, and STP whole brain analysis show differences throughout disease progression.ConclusionsWe utilized the well characterized 5XFAD model of AD to develop an integrated pipeline for deep phenotyping of novel mouse models of AD. This pipeline combines novel functional and anatomical assays across sites to track the ontology of AD progression, and targeted understanding of the molecular, biochemical and functional progression of AD pathology. Together, this pipeline provides a novel platform for greater understanding of LOAD mouse models and potential therapeutic approaches for AD.
Cerebral small vessel diseases are better associated with ambulatory than office blood pressure measurements
Authors: Melgarejo Jesus D. , Gutierrez Jose , Mena Luis Javier , Lee Joseph H. , Chavez Carlos A. , Calmon Gustavo , Silva Egle , Terwilliger Joseph Douglas , Vanassche Thomas , Verhamme Peter , Staessen Jan , Zhang Zhen‐Yu , Maestre Gladys E. 
Published: December 2020

AbstractBackgroundCerebral small vessel diseases (CSVD) is a forerunner of cognitive decline, vascular dementia, Alzheimer’s disease, and stroke. Which BP index is closest associated with CVSD remains unclear. We aimed this study to examine the association of BP levels, measured by the office and ambulatory BP monitoring (ABPM), with CSVDs, and to determine which BP indexes are better associated with CSVDs.MethodIn the Maracaibo Aging Study, 330 participants (73.3% women; mean age, 58.0 years) underwent ABPM, and magnetic resonance brain imaging to assess white matter hyperintensities (WMH), small artery disease (SAD), and silent brain infarcts (SBI), which were divided into total (SBIt), supratentorial (SBIs), and cortical (SBIc). Statistics included multivariable linear and logistic regression. In models including two BP indexes, we uncorrelated these indexes by regressing one index on the other and by using the residual of one BP index.ResultThe prevalence of SAD, SBIt, SBIs, and SBIc was 5.8%, 11.8%, 10.1%, and 6.1%; respectively. Multivariable models showed that office, 24‐h, daytime, and nighttime systolic BP (SBP) were significantly associated with WMH, SAD, SBIt, SBIs (P<0.05); all diastolic BP (DBP) indexes were related to WMH, but only nighttime DBP was associated to SAD and SBIs (P<0.05). Adjusted for office SBP, the 24‐h, daytime, and nighttime SBP remained significantly associated with WMH (P<0.01), whereas the opposite was for office SBP after adjustment by 24‐h or daytime SBP. With adjustment for office or daytime SBP, the association between SDA and SBIt with 24‐h and nighttime SBP remained significant (P<0.05); nighttime SBP was additionally related to SBIs. Daytime SBP was not associated with CVSD after adjustments by the office, 24‐h, or nighttime SBP. Adjusted for daytime DBP, nighttime DBP were significantly associated with SDA, SBIi, and SBIs (P<0.05).ConclusionCSVD was related to 24‐h and nighttime BP. Proper control of the ambulatory BP may reduce the risk for CSVD and associated adverse health outcomes.
Cortical microstructural changes and amyloid beta burden in cognitively normal subjective memory complainers
Authors: Chance Steven A , Torso Mario , Chiesa Patrizia Andrea , Lemercier Pablo , Vergallo Andrea , Lista Simone , Potier Marie‐Claude , Habert Marie‐Odile , Dubois Bruno , Hampel Harald ,   INSIGHT‐preAD Study Group
Published: December 2020

AbstractBackgroundThe aim of the present study was to investigate the association between brain amyloid β (Aβ) accumulation and cortical microstructural changes in cognitively normal individuals with subjective memory complaints.MethodA total of 258 individuals (100 males,158 females) from the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study [Dubois et al., 2018], were included. The 18F‐florbetapir PET images were used to compute whole brain and regional standard uptake value ratios (SUVr), while T1 structural and diffusion tensor imaging (DTI) scans were analysed to calculate 3 novel cortical grey matter diffusion measures (AngleR, PerpPD and ParlPD) and the mean diffusivity (MD) [McKavanagh et al., 2019]. A linear regression model was used to study the association between the global SUVr value and whole brain cortical diffusion measures, by including the diffusion measure as the dependent variable, and age, sex, APOE genotype and global amyloid SUVr as independent predictors. Partial correlation analysis, controlling for sex, was used to investigate regional associations between SUVr and diffusion values in 6 regions of interest (bilateral anterior cingulate, posterior cingulate, frontal superior orbital, inferior parietal, precuneus, middle temporal cortex). Results were considered statistically significant after false discovery rate correction (FDR <0.05).ResultLinear regression revealed that whole brain amyloid SUVr values were positively associated with whole brain AngleR (the angle between the principal diffusion direction and the radial minicolumn direction within the cortical grey matter) (β = 0.23, p<0.001). Regional partial correlations indicated significant associations between SUVr and AngleR regional values in left anterior cingulate cortex (r=0.168;p=0.010) and bilateral precuneus (left r=0.173;p=0.005; right r=0.178;p=0.004).ConclusionThese results showed a significant relationship between Aβ accumulation and cortical architectural change in subjective memory complainers. The regional associations revealed the presence of microstructural changes in key regions commonly affected in the early stage of AD [Palmqvist et al., 2017]. Our novel cortical DTI measures could offer additional information about cortical changes, playing a potential role as index of “neurodegeneration” in the ATN framework [Jack et al., 2018] of Alzheimer’s biomarkers.
Dual disclosure of APOE genotyping and amyloid PET results to cognitively normal older adults: A qualitative analysis
Authors: Lee Athene K.W. , Mandel Nicolas , Popescu Dominique , Williams Randal , Alber Jessica , Thompson Louisa I. 
Published: December 2020

AbstractBackgroundPreclinical Alzheimer’s disease (AD) is determined by biomarker risk assessment in cognitively normal individuals. Disclosure of risk is usually required for clinical drug trials targeting specific biomarkers (e.g., beta‐amyloid). More broadly, there is a growing movement towards participant engagement, which has fostered an interest in biomarker disclosure. Apolipoprotein‐E (APOE) genotype disclosure has been well researched, but less is known about dual disclosure of APOE and amyloid PET. Better understanding of how individuals and their families react to AD risk information will help refine the disclosure protocol.MethodQualitative interviews were completed with 15 individuals (aged 61‐73) and 10 study partners who received APOE (all e4 carriers) and amyloid PET (5 positive) results as part of clinical trial screening. Interview transcripts were coded for motivation to learn, result comprehension, emotional/behavioral impact, and decision to share results. Analysis aims to characterize APOE vs. PET disclosure experiences between participants and partners.ResultMotivation included altruism, worries about developing AD, and access to new information and treatment. Amyloid PET was viewed as a natural follow‐up to APOE genotyping or part of a comprehensive risk assessment, not a distinct test. Interestingly, most participants had already decided to learn about APOE and amyloid PET before informing their spouses, and in the case that their spouses disagreed, invited friends as study partners. Participants and partners consistently comprehended APOE as a remote risk factor and amyloid PET as more reflective of imminent AD pathology. However, those with negative PET understood that amyloid levels change over time, questioned how close they were to the threshold, and hoped for a repeat evaluation in the future. Most partners remembered the APOE disclosure more vividly than PET. Participants reported no change in memory complaints or worries about future decline regardless of risk level. Spouses rarely expressed concerns about the participant’s memory, were generally less worried about the results, and none observed memory changes after learning the risk level.ConclusionDual disclosure of APOE and amyloid PET appears to have minimal impact on perception of memory. Participants generally had stronger reactions to amyloid PET, while spouses had more vivid experience with APOE.
Psychological, brain, and hormonal factors associated with caregiver compassion fatigue, burnout, and stress
Authors: Beadle Janelle , Gifford Angela 
Published: December 2020

AbstractBackgroundThere are approximately 15 million family caregivers providing care to an individual with Alzheimer’s disease or a related dementia (Alzheimer's Association, 2015). Caregivers experience significant amounts of stress due to the challenging nature of providing care to older adults with Alzheimer’s disease and other chronic conditions. These stressors have been linked to dysregulation of hormones which can put caregivers at risk for a variety of diseases and can also negatively impact the brain. The present study (funded by the National Institute of General Medical Sciences) investigates the psychological, hormonal, and neural factors that are associated with compassion fatigue, burnout, and stress in caregivers to older adults with Alzheimer’s disease or other chronic conditions.MethodThe present study will characterize factors associated with greater caregiver compassion fatigue, burnout and stress through three aims: (1) Identify psychological and demographic factors; (2) Assess differences in brain network connectivity; (3) Measure differences in hormonal reactivity in response to emotional situations. The study is currently in the enrollment stage, and we are anticipating approximately 60 subjects by the end of the third year of the study.ResultBecause our study is still on‐going, we will discuss our preliminary results and anticipated outcomes. Pilot results show that caregivers report higher levels of momentary (state) empathy than non‐caregivers across different social contexts. Furthermore, preliminary findings demonstrate variability among caregivers in their cortisol reactivity to others’ suffering is linked to variability in prosocial behavior towards others. Other anticipated outcomes include that trait empathy will be associated with compassion fatigue, and that differences in connectivity between brain networks associated with stress and emotion will be associated with compassion fatigue and burnout.ConclusionThe results from this study will advance our understanding of key factors associated with compassion fatigue, burnout, and stress in caregivers to older adults with Alzheimer’s disease or other chronic conditions. This study will identify psychological, neural, and hormonal variables that may be useful in the development of interventions to improve caregiver well‐being.ReferenceAlzheimer's Association. (2015). 2015 Alzheimer's Disease Facts and Figures.