bluuebunny/crossref_metadata_2025_split huggingface dataset:
“I think they killed him”: Long‐term trauma associated with perceived cause of death in bereaved dementia caregivers whose loved ones were in a nursing home at time of death
Authors: Baker Zachary G , Nelson‐Kaigama Cindy , Klosterman Kate , Millenbah Ashley , Segundo Joahana , Nkimbeng Manka , Gaugler Joseph 
Published: December 2023

AbstractBackgroundOne in three Medicare beneficiaries dies with dementia. COVID‐19 has disproportionately increased death rates among: persons living with dementia (PLWD), those in nursing homes, and members racially/ethnically minoritized groups. Simultaneously, COVID‐19 led to a mass exodus of nursing home staff, creating a perfect storm for abuse and neglect, especially of those most often historically and systematically disadvantaged. Reports of abuse and neglect in nursing homes, especially among PLWD are not new. But, the primary focus has been residents being abused or neglected. In the present paper we present the implications of abuse and neglect for the family and friends who provide care for PLWD in nursing homes.MethodTogether with community partners we explored experiences of dementia‐related bereavement with a 15‐member community advisory board over two years. Our authorship team includes experts in long‐term care, healthcare system administrators, nurses who have worked within healthcare systems, and those with lived experience. Lived experience perspectives come from caregivers who cared for parents and grandparents with dementia, identify with different racial/ethnic groups, are of different ages, and have had between 2 and 12 years since the death of the PLWD they cared for.ResultAs one community member stated, “there’s all kinds of ways that a facility could potentially kill someone, whether it be through like a willful act or just neglect.” We present the experiences of community partners who attribute the deaths of PLWD they cared for to such abuse and neglect and explore the ways that abuse and neglect manifested, potential precipitating events, and how those deaths continue to affect family members years or even decades after a PLWD’s death.ConclusionWe explore and share these experiences to amplify the voices of these bereaved dementia caregivers and raise a call for the research and clinical communities to seek ways to aid former caregivers and nursing home staff. Community partners also made clear that interactions between each person with dementia and nursing home staff were exceedingly challenging and that those staff deserve additional support to help them prepare for and cope with those events.
EEG correlates in the three variants of Primary Progressive Aphasia
Authors: Cecchetti Giordano , Agosta Federica , Basaia Silvia , Cividini Camilla , Cursi Marco , Canu Elisa , Leocadi Michela , Santangelo Roberto , Caso Francesca , Fanelli Giovanna Franca , Minicucci Fabio , Magnani Giuseppe , Filippi Massimo 
Published: December 2023

AbstractBackgroundThe analysis of EEG cortical sources is promising for the investigation of neurodegenerative disorders. The aim of this study is to explore its value in the characterization of the three clinical presentations of primary progressive aphasia (PPA).MethodA resting‐state 19‐channel EEG was obtained in 48 patients diagnosed with PPA (21 nonfluent/agrammatic variant PPA [nfv‐PPA], 18 logopenic variant PPA [lv‐PPA], 9 semantic variant PPA [sv‐PPA]) and in 21 matched healthy controls. Using eLORETA, EEG current source density (CSD) values were estimated at voxel‐level and compared among groups of patients and controls.ResultPatients showed a low‐to‐moderate cognitive impairment. Lv‐PPA cases showed a higher delta density over the left frontal and temporal regions when compared to sv‐PPA subjects, and in left precuneus and posterior cingulate when compared to nfv‐PPA patients. They also displayed a higher delta density in left frontal, parietal and temporal regions than healthy subjects, and lower alpha1 density in left occipital regions compared with other patient groups. Lv‐PPA patients also showed reduced alpha2, beta1 and beta2 density over the left occipital regions when compared to healthy subjects. No significant differences were found in terms of CSD among sv‐PPA, nfv‐PPA and healthy subjects.ConclusionConsistently with our previous studies, findings in PPA patients suggest that Alzheimer’s disease (AD), but not fronto‐temporal degeneration (FTD), might induce a characteristic disruption of the cortical electrical activity, detectable by EEG. EEG might thus help in the differential diagnosis between AD‐related and FTD‐related PPA variants.
Sex differences in baseline sleep and dark phase rebound sleep after chronic sleep fragmentation in the APPXPS1 and 5XFAD mouse models
Authors: Duncan Marilyn J. , Johnson Carrie E , Guo Landys , Barth Sarah , Buzinova Valeria , Padgett Samantha , Turton Savannah , Jessup Michael Tyler , McCarty Leanna M , Beechem Lindsay E , Briones William , Subramoniam Anjana , Whitlock Haleigh R , Sucharski Michael , Bosh Kimberly , Kohler Katharina , Macheda Teresa , Bachstetter Adam D , Sunderam Sridhar , O'Hara Bruce F. , Murphy Michael Paul 
Published: December 2023

AbstractBackgroundFragmentation of the daily sleep‐wake rhythm is a risk factor for Alzheimer’s disease (AD) (Li et al, Lancet Healthy Longev 1:e96‐e105 [2020]). While women have a higher AD incidence than men, whether women are more sensitive to sleep fragmentation (SF) is not known. Studies in female 3xTg‐AD mice (8‐11 months old) show that chronic SF for four weeks alters the daily sleep‐wake rhythm and stimulates AD‐like neuropathology (Duncan et al, Neuroscience 481:111‐122 [2022]).MethodTo investigate possible sex differences in the effects of sleep fragmentation, we studied two AD mouse models and matching wild‐type controls, APPxPS1‐knock‐in mice (6.2‐11 months old; N = 127) and 5XFAD mice (2.3‐3.3 months old; N = 52). All mice were exposed to 3‐4 weeks of SF or undisturbed sleep while individually housed in cages interfaced for piezo electric sleep recording for monitoring of daily sleep‐wake rhythms. SF consisted of four daily sessions (1 hour each) of enforced wakefulness (induced with toys and paintbrush stimulation) that were evenly distributed during the light phase, for 5 days/week. Immediately after the last SF session, mice in both groups were euthanized and cortical and hippocampal tissue was dissected and frozen. Amyloid‐beta levels were determined in soluble fractions using ELISA.ResultsSF redistributed sleep from the light phase (loss) to the dark phase (gain) in APPxPS1‐ki (p<0.0001) and 5XFAD (p<0.05) mice and WT controls. Overall, females slept less than males (p<0.001) and were more affected by SF. Dark phase “rebound” sleep after SF was greater in APPxPS1‐ki females (∼70% of undisturbed controls) than in APPxPS1 males or WT mice of either sex (∼20% of undisturbed controls) (p<0.001). Cortical amyloid‐beta levels were higher in female than male AD mice, but surprisingly, neither cortical nor hippocampal amyloid‐beta levels were affected by SF in either strain.ConclusionThese findings suggest an interaction between sex, AD mutations, and neuropathology on dark phase rebound sleep after chronic SF. To elucidate this interaction, on‐going studies are investigating the role of amyloid‐beta in sex‐differences in SF‐induced rebound sleep and potential sex differences in SF effects on gene expression in brain regions regulating sleep or circadian rhythms.
Association of neuropathological lesions with body mass index by the time of death
Authors: Reis Ururahy Raul , Val Marina Scott , Ciciliati Aline Maria Macagnan , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Rodriguez Roberta Diehl , Grinberg Lea T. , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundThe association between moderate/severe dementia and lower Body Mass Index (BMI) is well described, but the weight decline seems to also occur in cognitively normal individuals with preclinical dementia. Considering that up to one‐fifth of individuals with normal cognition might meet the criteria for a neuropathological diagnosis, autopsy studies are key detecting neurodegenerative and cerebrovascular diseases that could be underlining weight changes during the life course. Therefore, we investigated the association between dementia‐related brain lesions and BMI and evaluated whether cognitive function was a mediator of this association.MethodNeuropathological study in a population‐based sample of 1,170 Brazilians. Clinical variables and cognition evaluation were obtained through a post mortem interview with a proxy. Linear regression adjusted models were used to investigate the association between each neuropathologic lesion (independent variable) and the BMI (dependent variable). The direct and indirect (considering a mediation by cognitive abilities) effects of each neuropathologic lesion on BMI were evaluated through a mediation model.ResultIndividuals with lower body weight were more likely to have a higher burden of neuropathological lesions and worse cognitive abilities. Neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI. Mediation analyses showed these lesions were directly associated with BMI and indirectly through cognitive abilities. Despite having normal cognitive abilities, 25% of the sample had at least one neuropathologic diagnosis. High NFT burden was associated with lower BMI even in these participants.ConclusionNeurofibrillary tangles were associated with lower BMI independent of cognitive abilities.
Prediction of longitudinal cortical amyloid deposition based on cerebrospinal fluid biomarkers for Alzheimer’s disease in cognitively unimpaired individuals: the role of APOE‐ε4
Authors: Rizzo Marianna , Oomens Julie Elisabeth , Jansen Willemijn J. , Gispert Juan Domingo , Ritchie Craig W , Jessen Frank , Rovira Mercè Boada , Marquié Marta , Hanseeuw Bernard J , Schmidt Mark E , Stephens Andrew W. , Gismondi Rossella , Frisoni Giovanni B , Farrar Gill , Barkhof Frederik , García David Vállez , Collij Lyduine E. , Alves Isadora Lopes , Visser Pieter Jelle , Vos Stephanie J. B. ,   the AMYPAD Consortium
Published: December 2023

AbstractBackgroundThe relationship between cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), APOE‐ε4 and longitudinal cortical amyloid deposition in preclinical AD is relevant for AD trial design but remains unclear. Thus, we aimed to investigate longitudinal cortical amyloid accumulation on PET as predicted by baseline CSF AD biomarker profiles and APOE‐ε4 carriership in cognitively unimpaired individuals.MethodWe selected 330 cognitively unimpaired individuals from 6 cohorts of the AMYPAD study. All had available baseline data on CSF aß1‐42 (A), p‐tau181 (T), APOE‐ε4 carriership (yes/no), and baseline and follow‐up amyloid PET data. To evaluate different AD stages, individuals were classified as A‐T‐, A‐T+, A+T‐, or A+T+ based on CSF biomarker abnormality using center‐specific cut‐offs. We used a continuous outcome measure of global cortical amyloid deposition on PET expressed in centiloids. Analyses were performed in the total sample and stratified for APOE‐ε4, using generalized linear mixed models with random intercepts and slopes, adjusted for age and sex.Result58% were female, 49% APOE‐ε4 carriers, and mean age was 64+‐6.1 years, with an average follow‐up of 3 years. 170 individuals were A‐T‐, 70 A‐T+, 59 A+T‐, and 31 A+T+. Baseline cortical amyloid deposition was different between all groups, with A+T+ having the highest deposition, followed by A+T‐, A‐T+ and A‐T‐ (Figure 1, Table 1). Longitudinally, all groups showed increased amyloid deposition, except A‐T‐. Moreover, A+ groups showed greater increases in longitudinal amyloid deposition than A‐ groups. In APOE‐ε4 carriers, all AT groups showed increased longitudinal amyloid deposition, while in non‐carriers, A‐T+ and A‐T‐ did not (Figure 2, Table 1). Only in APOE‐ε4 carriers, A+T+ showed greater increases in longitudinal amyloid deposition than A+T‐, with A+T‐ showing a similar longitudinal deposition as A‐T+.Conclusion
APOE‐ε4 impacts the association between CSF AD biomarkers and longitudinal amyloid PET deposition in cognitively unimpaired persons. Amyloid‐negative APOE‐ε4 carriers could be at an early AD stage, as they showed increased cortical amyloid longitudinally, independent of baseline p‐tau status. In amyloid‐positive persons, p‐tau abnormality related to higher baseline cortical amyloid, but only in APOE‐ε4 carriers to steeper increases in cortical amyloid longitudinally. This has important implications for AD trial design.
Role of a cellular thermal shift assay on evaluation of drug‐target engagement for compound selection
Authors: Mason Emily R , Chu Shaoyou 
Published: December 2023

AbstractBackgroundIdentification of small molecule‐target engagement is important for target‐based drug discovery. To support drug discovery efforts for Alzheimer’s Disease, we developed and implemented cellular thermal shift assays (CETSA) based on HiBiT/LgBiT reconstituted NanoLuc method (Promega). Advantages of the CETSA are testing target engagement in an intact cellular context, simple mix‐and‐read procedures, and high capacity to meet drug discovery project needs.MethodStable cell lines (HEK293t or HMC3) expressing HiBit (11 amino acids; Promega) tagged target were established. The CETSA uses Nano‐Glo HiBiT Lytic Detection kit (Promega) to detect abundance of undenatured HiBit‐tagged target protein in cells, while heat caused protein aggregates to be mostly undetectable. The CETSA procedures are 1) plating cells into 96‐well PCR plates; 2) treating cells with compounds for 60 min in 37 oC incubator; 3) heating cell plates for 3 min in a PCR machine; 4) processing with Nano‐Glo HiBiT Lytic Detection kit (10 min) and reading plates for luminescence. Before testing compounds, an Tagg (temperature at 50% maximal signal during aggregation) for each target was determined and used as baseline. When a compound engages the target, it caused Tagg shifts that can be quantified by the assay.Result1) Tagg is target specific, with INPP5D Tagg = 44.2 °C and PLCG2 Tagg = 45.9 °C. 2) Screening compounds at 100 µM on cells and heated at Tagg, the luminescent signal changes (compared to untreated control) suggesting compound‐target engagement. 3) The CETSA with compound dosing and heating at Tagg was used to confirm the compound engagement. 4) The HiBit tag control CETSA with compound dosing and Tagg heating was used to find non‐specific binders. The assay platform has been implemented for drug discovery efforts targeting INPP5D and PLCG2 respectively; example data will be shown.ConclusionThe CETSA platform is efficient, reproducible and has high capacity, making it well‐suited to target based drug discovery research. Application of the CETSA on projects targeting INPP5D, PLCG2 of microglia has facilitated compound selection based on confirming molecule target engagement, which allowed our project team to quickly focus on selected compounds for further studies.
Isolated REM sleep behaviour disorder in the Tasmanian ISLAND Sleep Study: prevalence and profiles of prodromal dementia
Authors: Bramich Samantha , King Anna E , Noyce Alastair J , Bindoff Aidan D , Kuruvilla Maneesh , Naismith Sharon L , Bartlett Larissa , Vickers James C , Alty Jane E 
Published: December 2023

AbstractBackgroundIdentifying people with isolated REM sleep behaviour disorder (iRBD) provides important opportunities for targeted dementia prevention as iRBD is a prodrome of Lewy Body dementia (LBD) and other neurodegenerative diseases (NDD). There have been no prevalence studies of iRBD in Australia and little is known about whether associated motor, cognitive, olfactory and circadian features influence the progression to different NDD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study aims to identify the iRBD prevalence in Tasmania and determine how different iRBD profiles predict progression to dementia and other NDD.MethodAdults aged 50+ years in Tasmania completed online questionnaires including the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ), RBD single question screen (RBD1Q), Pittsburgh Sleep Quality Index (PSQI), and questions regarding dreaming, autonomic, motor s, and pain symptoms.Result2,905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have ‘probable’ iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%).Conclusion2905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have ‘probable’ iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%).
Association of Common and Rare Variants with Alzheimer’s Disease in 16,905 individuals with Whole‐Genome Sequence Data from the Alzheimer’s Disease Sequencing Project
Authors: Lee Wan‐Ping , Choi Seung Hoan , Schellenberg Gerald D. , DeStefano Anita L. , Haines Jonathan L. , Peloso Gina M. ,   Collaboration on Alzheimer’s Disease Research (CADRE)and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
Published: December 2023

AbstractBackgroundWhole genome sequencing (WGS) data enables assessment of common and rare variants for association with human diseases. Here we report our analysis using ADSP R3 WGS data to discover genetic variants associated with AD.MethodWe performed association testing of common variants (minor allele frequency [MAF] > 0.5%) as well as aggregates of rare (MAF < 1%) coding and non‐coding variants. Given that ADSP is composed of multiple ancestry groups, we performed association testing across all participants (pooled population [PP], Ncases = 6,519 and Ncontrol = 6,852) and within the following populations: African Americans (AA, Ncases = 1,137 and Ncontrol = 1,707), Hispanics (HIS, Ncases = 1,021 and Ncontrol = 1,988), and Non‐Hispanic White (NHW, Ncases = 4,230 and Ncontrol = 3,109) defined by self‐reported race and ethnicity (Table 1).ResultAs expected, our most significant associations are at the APOE locus (chr19:44,905,796‐44,909,393) (Figure 1). In the pooled‐population analysis, we observed known AD associations for BIN1 (p = 3.2×10−09) variants with AD status. In the NHW analysis, we observed AD associations for variants in CR1 (p = 7.97×10−08), BIN1 (p = 2.16×10−08), ARHGEF33 (p = 4.85×10−8), ANK3 (p = 1.43×10−12) and MYCBP2‐AS1 (p = 4.59×10−08), and in the AA analysis, we observed a significant variant near LINC00320 (p = 1.5×10−8). In the HIS subset, a region (chr14:72,698,038‐75,846,454) has 31 significant variants (p = 3.9×10−11) crossing multiple genes. This region covers PSEN1 G206A (rs63750082), a well‐known early‐onset AD mutation. Local‐ancestry analysis shows that the mutations, including G206A, are of African ancestry. Using kinship coefficients calculated within this dataset, it was determined that the signals are not driven by a familial linkage disequilibrium.We observed gene‐based aggregation of coding variants in PSEN1 in the pooled‐population and HIS analyses (p<5×10−8) (Figure 2). In our gene‐centric noncoding aggregates analysis, we identified noncoding variants in the promotor of TOMM40 in the pooled‐population analysis (p = 7.2×10−08). After adjusting for APOE e4 (rs429358) and e2 (rs7412) alleles, there was an attenuation, but the association remained suggestive (p = 7.1×10−06).ConclusionWe performed common and rare association analysis of AD on ADSP WGS data. We observed associations with variants in known AD loci. We also observed population‐specific associations and an association of AD with rare noncoding variants in TOMM40, indicating WGS in diverse populations can lead to novel genetic associations with AD.
Statistical Physics of Fitness Landscapes Finds Risk Genes Specific to Different AD Genetic Backgrounds
Authors: Lagiesetty Yashwanth , Samieinasab Maryam , Al‐Ramahi Ismael , Wilhelm Kevin , Katsonis Panagiotis , Asmussen Jenn , Lee Kwanghyuk Danny , Botas Juan , Lichtarge Olivier 
Published: December 2023

AbstractBackgroundTo study how genetic backgrounds modulate neurodegenerative risk requires genotype‐phenotype association methods effective in small patient cohorts.MethodWe developed a genome sequence analysis framework rooted in Statistical Physics, which yields a reliable measure of gene functional impact in any chosen population. When comparing two populations, such as cases and controls, shifts in gene importance identify those likely to drive phenotype differences.ResultsIn repeated case‐control genome sequence studies of Alzheimer’s Disease (AD) focused on a single sex, APOE allele, or ethnic ancestry, we identified gene sets that met criteria for success, including prior GWAS studies, post‐mortem of AD brain tissues expression, live Drosophila experiments, and risk modeling.ConclusionStatistical Physics of fitness landscape is a new tool to characterize genes and mutations that enhance or protect from AD, powerful enough to identify similarities, complementarities, and differences in risk gene in target subgroups of about 1000 subjects.
An 8‐week program of computerized cognitive training with exercise impacts cortical grey matter in older adults: Secondary findings of a randomized controlled trial
Authors: Stein Ryan G , Brinke Lisanne F , Silva Nárlon Cássio Boa Sorte , Handy Todd C , Hsiung Ging‐Yuek Robin , Liu‐Ambrose Teresa 
Published: December 2023

AbstractBackgroundThe world’s population is aging and thus, it is important that we find strategies to reduce the rate of age‐related cognitive decline. Lifestyle interventions can play an important role in delaying the onset of cognitive decline. Evidence shows both computerized cognitive training (CCT) or exercise can improve cognitive function. However, the effect of CCT on cortical structure is not well understood. This study examines the effect of 8‐weeks of CCT, with or without a preceding exercise bout, on cortical structure in community‐dwelling older adults.MethodStructural magnetic resonance imaging (MRI) data acquired from an 8‐week, 3‐arm, proof of concept randomized controlled trial was used. Participants (N = 125) aged 65 – 85 were randomized (1:1:1) to either 8 weeks of 3x/week: 1) Balance and Toned (BAT; active control); 2) CCT; or 3) Exercise + CCT (Ex‐CCT). Measurement occurred at baseline and trial completion (i.e., 8‐weeks). Fifty‐three participants with baseline and trial completion MRI data were included in this analysis. Freesurfer was used to assess BAT vs. CCT, BAT vs. Ex‐CCT, and CCT vs. Ex‐CCT differences in cortical thickness and volume at trial completion, adjusting for age, sex, and Montreal Cognitive Assessment (MoCA) score.ResultAt trial completion, CCT vs. BAT decreased left rostral middle frontal gyrus volume (cluster size = 553.51 mm2, cluster‐wise p = .027) and left superior temporal gyrus thickness (cluster size = 525.58 mm2, cluster‐wise p = .039). Ex‐CCT vs. BAT increased cortical thickness in the left (cluster size = 900.23 mm2, cluster‐wise p = .001) and right (cluster size = 681.95 mm2, cluster‐wise p = .020) superior parietal gyri. Finally, Ex‐CCT vs. CCT increased left cuneus thickness (cluster size = 1062.12 mm2, cluster‐wise p < .001) as well as right post central gyrus thickness (cluster size = 714.85 mm2, cluster‐wise p = .005) and volume (cluster size = 1030.08 mm2, cluster‐wise p < .001).ConclusionEight weeks of CCT with exercise is of sufficient duration to induce structural change in the brain. Moreover, exercise may enhance the effect of CCT on cortical grey matter structure vs. CCT alone.