bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovering genetic variants contributing to sleep dysfunction in presymptomatic Alzheimer’s mice
Authors: Hadad Niran , Dunn Amy R. , O'Connell Kristen M.S. , Kaczorowski Catherine C. 
Published: December 2020

AbstractBackgroundDisordered sleep is frequently observed in Alzheimer’s disease patients. Sleep loss is associated with increased Aβ and tau accumulation in both AD patients and model organisms. Furthermore, cognitively intact individuals with impaired sleep are at higher risk for AD. Although individual differences in sleep are known to be highly heritable, little is known of the genetic factors associated with sleep dysfunction in aging and AD and if these contribute to disease development.MethodSleep was assessed at a presymptomatic age (6‐7 months) in a panel of genetically diverse mice carrying familial AD mutations, which better models complex etiology of human AD (AD‐BXDs; Neuner et al 2019). Sleep‐wake activity was measured for five consecutive days using the PiezoSleep tracking system across 25 AD‐BXD strains and their nontransgenic littermates (Ntg‐BXD).ResultAD‐BXD mice slept significantly less during the dark cycle compared to Ntg‐BXDs. Additionally, reduction of sleep was observed during the transition from dark to the light cycle, suggesting disruption of circadian function. Females slept less than males regardless of AD mutation status. We identified a significant quantitative trait locus (QTL) on chromosome 9 associated with total sleep, this region is syntenic with a regions on the human chromosome 11, harboring six sleep‐associated human GWAS SNPs, demonstrating the relevance of this region to human biology. Additionally, we identified a QTL for hourly sleep at ZT14 that mapped to intron 1 of the gene Kirrel3 of chromosome 9 (∼20 mb downstream of the sleep‐QTL). Differential gene expression implicates Kirrel3 as a novel target‐gene for validation.ConclusionWe provide the first evidence that genetic factors interact with AD mutations to influence sleep behavior, and identified two regions causally associated with variation in sleep in the AD‐BXDs. Mouse‐to‐human comparison suggest that both region are relevant to humans, demonstrating the value of the AD‐BXDs as a translational AD model. Future work will leverage genome engineering to correct sleep‐associated variants to test the delay or prevention of cognitive deficits onset apparent in the AD‐BXDs by 14 months of age. These studies may identify novel therapeutic targets to treat AD dementia.
Multifaceted pattern of longitudinal imaging changes in cognitively normal midlife adults: The PREVENT‐Dementia study
Authors: Mak Elijah , Dounavi Maria‐Eleni , Low Audrey , McKiernan Elizabeth , Carter Stephen F , Newton Coco , Williams Guy B , Ritchie Karen , Wells Katie , Sahin Zeynep , Carriere Isabelle , Terrera Graciela Muniz , Ritchie Craig W. , Su Li , O'Brien John T. 
Published: December 2020

AbstractBackgroundFirst‐degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Identifying preclinical brain changes would facilitate both early quantifiable longitudinal disease monitoring and interventional trials. However, the literature of imaging changes in FH+ remains highly controversial. We aim to investigate “estimated years to onset of dementia” (EYOD) as a surrogate marker of preclinical progression and assessed whether FH+ approaching the onset of dementia would express more severe patterns of longitudinal brain changes.Method89 FH+ persons underwent serial 3T‐MRI with T1‐MPRAGE, DWI and ASL (mean interval: 2 years). The longitudinal Freesurfer pipeline was used to segment hippocampal subfields and early‐AD regions. Partial‐volume corrected ASL data and DWI data were processed with FSL‐BASIL4 and DTI‐TK5. Small vessel disease was indexed with white matter hyperintensities (WMHs) (Figure 1). We applied linear mixed effects models with random intercepts to predict MRI changes relative to baseline EYOD, accounting for baseline age, gender, education and time from baseline. Secondary analyses examined the interaction of APOE‐ε4+ on proximity‐related brain changes.ResultA shorter EYOD was associated with progressive decrease in FA, increase in MD/RD and atrophy of the fusiform gyrus over time (Figure 2). Interaction analyses revealed that APOE‐ε4+ carriers showed significant longitudinal atrophy of the hippocampal subfields with shorter EYOD. In contrast, cortical perfusion increased before plateauing ∼10 years before estimated onset. There were no associations of EYOD with mean cortical thickness or WMHs (See Figure 3 for a summary of main findings).ConclusionOur findings represent an extensive characterisation of longitudinal brain changes associated with proximity to dementia in FH+. Individuals who are approaching their parental age of dementia onset may be showing incipient brain abnormalities, particularly amongst APOE‐ε4 carriers. The involvement of early‐AD regions also confer support to the biological validity of EYOD as a stage marker of preclinical progression. Further clinical follow‐up of our sample would provide critical validation of these findings.
Caregiver‐centered care health workforce competencies: Taking steps to support family caregivers of people living with dementia throughout the care trajectory
Authors: Parmar Jasneet , Poole Lisa , Anderson Sharon Dorothy , Duggleby Wendy , Holroyd‐Leduc Jayna , Brémault‐Phillips Suzette , Pollard Cheryl , Charles Lesley , Haq Anwar 
Published: December 2020

AbstractBackgroundFamily caregivers [FCGs] are the backbone of the health system [1‐3]. They provide over 80% of the care for people with dementia, chronic illnesses and impairments [4 5]. Despite evidence of their contributions and consequences of caregiving, support for FCGs has not been a health system priority[6‐8]. Multi‐level interdisciplinary Alberta stakeholders recommended developing Caregiver‐Centered Care Education for the health workforce to fill this gap [9‐14]. Education to prepare health providers to effectively identify, engage, assess, and support FCGs throughout the care trajectory is an innovative approach in addressing inconsistent system of supports for FCGs [5 6 15‐17]. Objective: We report on development and validation of the Caregiver‐Centered Care Competency Framework to help with curricular design and subsequent evaluation of effectiveness of care providers working within healthcare settings to engage and support FCGs. Project description: We used a modified Delphi approach. In the first 2 rounds, multi‐level, interdisciplinary participants, rated the indicators in terms of importance and relevance. In the 3rd round consensus meeting, participants validated the final competency indicators in small group sessions. Participants: Expert panel of international, national, and provincial stakeholders were invited to a 2‐day symposium March 14‐15, 2019 and participate in the Modified Delphi Process.ResultsAn expert panel of 42 international, national, and provincial stakeholders participated. Thirty‐four experts (81%) participated in the round 1, 36 (85.7%) in round 2, and 42 people (100%) in round 3. There was stable consensus across all three rounds, 96.07% of participants rated the indicators as essential or important (Round 1, 95.81%; Round 2, 94.15; Round 3, 98.23%). Six competency domains, including indicators, were validated. Discussion: FCG research has been primarily focused on educating FCGs to provide care [18‐20]. Our stakeholder engagement processes [9‐14] is critical to intervention research and practice that supports FCGs. The direct inclusion of multilevel stakeholders, particularly the FCGs, provided a robust forum for discussion and increased consensus around the value of a healthcare workforce trained to support FCGs.ConclusionsThese competencies will shape the design of educational curricula and interdisciplinary training programs aimed at supporting the health and social care workforce to provide caregiver‐centred care.
IBC‐Ab002, an anti‐PD‐L1 monoclonal antibody tailored for treating Alzheimer’s disease
Authors: Baruch Kuti , Kertser Alexander , Matalon Omri , Forsht Ofir , Braiman Shai , Shochat Eliezer , David Carol , Yoles Eti 
Published: December 2020

AbstractBackgroundThe ongoing cross‐talk between the immune system and the central nervous system plays a major role in healthy brain tissue maintenance, with critical implications to brain aging and neurodegeneration. Based on the innovative concept of “protective autoimmunity”, established by Schwartz and her group, it was shown that targeting the programmed cell death receptor (PD)‐1 / PD‐L1 pathway evokes an immune response that supports recruitment of specialized immune cells (primarily of myeloid origin) to the brain territory, where these cells act by enhancing clearance of toxic elements, improving neuronal function, and reducing inflammation in mouse models of Alzheimer's disease (AD) and dementia. Maintaining a long‐lasting effect was found to be dependent on intermittent treatment course. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody that was designed, by point mutations on its Fc backbone, to fulfil the pharmacokinetics (PK), pharmacodynamics (PD) and safety characteristics anticipated for treating AD. Antibody optimization and lead selection will be presented.MethodsCorrelation between PK, PD, and antibody efficacy and safety, was evaluated using different antibody variants that share the same variable region, but differ in their physical properties due to point mutations in their Fc region. These studies, in mouse models of AD and in healthy cynomolgus monkeys, were used for modeling human PK/PD properties of IBC‐Ab002.ResultsPharmacological studies in mice revealed that treatment efficacy is primarily Cmax‐dependent, rather than exposure‐dependent. Biomarkers for biological activity were identified in the blood of both treated mice and monkeys, and PK/PD relationships were used to predict IBC‐Ab002 PK and effective dose range in humans. The ability to maintain treatment efficacy using intermittent administration regimen was evaluated in a longitudinal study, and found to be effective for up to 6 months from treatment initiation. Using a mouse model that spontaneously develops autoimmune diabetes, we also show that the chosen antibody modifications significantly improve its safety profile.ConclusionsIBC‐Ab002 antibody was selected for clinical development based on its unique characteristics, tailored for the mechanism of action intended for treating AD, and superior safety profile in terms of immune‐related adverse events. We are currently planning the first‐in‐human study of IBC‐Ab002 in AD patients.
Impact of sex and APOE E4 on age‐related cerebral blood flow trajectories in cognitively asymptomatic middle‐aged and older adults: A longitudinal study
Authors: Wang Rui , Oh Jennifer M. , Motovylyak Alice , Ma Yue , Sager Mark A. , Rowley Howard A. , Johnson Kevin M. , Gallagher Catherine L. , Carlsson Cynthia M. , Bendlin Barbara B , Johnson Sterling C. , Asthana Sanjay , Eisenmenger Laura , Okonkwo Ozioma C. 
Published: December 2020

AbstractBackgroundReduced cerebral blood flow (CBF) has been considered as a potentially early biomarker of late‐onset Alzheimer’s disease (AD). We sought to detect the pattern of age‐related CBF trajectories, and to investigate how these trajectories are affected by APOE, chromosomal sex, and cardiometabolic measurements.MethodFrom two ongoing longitudinal cohort studies—the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer’s Disease Research Center—we included 950 individuals (age range 40—89 years), who were cognitively unimpaired at their first visit. CBF was measured using pseudo‐continuous arterial spin labeling MRI. Demographic factors, APOE ɛ4 status, and cardiometabolic measurements were obtained during a clinic visit that included structured interviews, physical examinations, and blood sampling. We applied linear mixed‐effects models in our analyses, which focused on brain regions of relevance to AD.ResultDuring the follow‐up period (median 2.17 years, range 0.13—8.24 years), increasing age was significantly associated with decreasing CBF in total gray matter (β=‐1.54) (Figure, a), hippocampus (‐1.33), superior frontal gyrus (‐1.92), middle frontal gyrus (‐2.20), posterior cingulate (‐2.71), and precuneus (‐2.32), with all p‐values<0.01. A three‐way interactive effect of age, sex, and APOE ɛ4 allele was observed on CBF trajectories. That is, compared with male ɛ4 carriers, female ɛ4 carriers showed a faster decline in global and regional CBF with increasing age (Figure, c), whereas age‐related decline in CBF was similar between male and female ɛ4 non‐carriers (Figure, b). Worse cardiometabolic profile (i.e., increased systolic blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower CBF at all the visits. When time‐varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE ɛ4 on age‐related CBF trajectories became largely attenuated.ConclusionOur findings demonstrate that APOE genotype and sex interactively impact CBF trajectories across the lifespan, and that this effect may be partially explained by cardiometabolic alterations.
A novel visual short‐term memory task differentiates MCI and Alzheimer’s patients from healthy ageing
Authors: Toniolo Sofia , Maio Maria R. , Tabi Younes Adam , Slavkova Elitsa , Plant Olivia , Saleh Youssuf , Attaallah Bahaaeddin , Idris Imran , Peixoto Joao , Preul Christoph , Srowig Annie , Joedecke Steffen , Butler Christopher , Thompson Sian , Manohar Sanjay , Finke Kathrin , Husain Masud 
Published: December 2020

AbstractBackgroundWe developed a novel delayed reproduction task, the “What was where?” task, which obtains a continuous measure of localization error and is more sensitive compared to conventional span measures of Short‐term Memory (STM).MethodWe recruited 44 MCI (Mild Cognitive Impairment), 41 AD (Alzheimer’s Disease) patients and 109 healthy elderly controls (EHCs) from memory clinics in Oxford, UK and Jena, Germany, where they performed the “What was where?” task (Figure 1). We extracted the following metrics: Identification Accuracy (percentage correctly identified items), Absolute Localization Error (how far the object was misplaced), Misbinding rate (erroneously localizing an item to the remembered location of another item in memory) and Guessing response rate.ResultAbsolute Localization Error and Misbinding rates were greater in MCI and AD patients (p < 0.001) compared to EHCs, while AD and MCI performed similarly on these metrics. However, Identification Accuracy as well as Guessing (p = 0.003) were greater in MCI (p < 0.001) compared to AD patients. Moreover, EHCs identified the correct object more often (p < 0.001) and guessed less (p < 0.001) than MCI patients.ConclusionThis novel task is able to detect STM impairment in MCI cases on a continuous scale, and is a sensitive memory measure which might be a useful index of memory for future clinical trials in AD in its earliest stages.
Longitudinal changes of automated speech measures in natural connected speech in ALS
Authors: Shellikeri Sanjana , Cho Sunghye , Ash Sharon , Parjane Natalia , Elman Lauren , McMillan Corey T , Grossman Murray , Nevler Naomi 
Published: December 2020

AbstractBackgroundAmyotrophic Lateral Sclerosis (ALS) is a multi‐system neurodegenerative disorder with motor and cognitive deficits. Speech is affected both by motor processes associated with the articulation of utterances and by cognitive processes related to conveying a linguistic message. Previous studies in ALS have reported reduced speaking rate, longer pause durations, and more pause events compared to healthy controls. However, existing studies are scarce, rarely compare the effects of motor versus cognitive deficits, and have not yet characterized longitudinal changes in this population. In this study, we analyzed longitudinal changes in speech acoustic features in ALS from 1‐minute speech samples using an objective, reproducible, fully automated method.MethodWe examined digitized Cookie Theft picture descriptions produced by 21 native English‐speakers (66.7% males, mean (SD) age (y) = 65.3 (11.2); education (y)= 15.2 (2.6)) with ALS for up to 6 years (mean inter‐sample interval= 12.8 months, median samples/subject = 3). We automatically segmented each sample into speech and pause segments and extracted total speech = sum of speech segment durations (sec); total time = sum of speech and pause segment durations (sec); average speech and pause segment durations (sec); and speech frequency and fragment rate = number of speech events per 60 sec of total time and total speech, respectively. Longitudinal changes were related to cognition (ALS‐Specific Edinburgh Cognitive and Behavioral ALS Screen scores (ALS‐sp. ECAS)), motor features (ALS Functional Rating Scale–Revised scores (ALSFRS‐R)), and progression rate (change in ALSFRS‐R over disease duration) using linear mixed‐effects models with interactions between time and the predictor of interest.ResultLower scores on ALS‐sp. ECAS were predictive of an increase in pause durations (p=.023) and a reduction in total time (p = .019) over time. Higher ALSFRS‐R scores were predictive of increased speech fragment rate (p=.013) over time. Faster progression rates were associated with longer pauses (p=.006) and reduced speech frequency (p=.001) over time.ConclusionSpeech acoustic measures are differentially impacted by motor versus cognitive features over the disease course in ALS. Longitudinal speech changes in ALS can be characterized using automated methods of acoustic analysis natural speech.
Study partner perspectives on disclosure of amyloid PET scan results
Authors: Largent Emily A , Abera Maramawit , Harkins Kristin , Roberts J Scott , Karlawish Jason ,   REVEAL‐SCAN Team
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) secondary prevention trials typically require cognitively unimpaired individuals to learn the results of an amyloid PET scan. Additionally, they are required to enroll with a study partner who serves as a knowledgeable informant and often learns the participant’s amyloid PET scan result. The purpose of this study is to understand how study partners understand and experience the disclosure of another person’s amyloid PET scan result.MethodParticipants in this qualitative study are study partners of cognitively unimpaired adults aged 60–75 years who learned their amyloid PET scan result as part of Risk Evaluation and Education of Alzheimer’s Disease: The Study of Communicating Amyloid Neuroimaging (REVEAL‐SCAN; NCT02959489). The sample was recruited to be balanced on the REVEAL‐SCAN participants’ amyloid PET scan results (i.e, “elevated” or “not elevated”) and the nature of participant‐study partner relationships (i.e., spousal or non‐spousal). We have interviewed 80 study partners. All interviews were recorded, transcribed, and coded in NVivo 12.0. The University of Pennsylvania IRB approved this study.ResultMost study partners knew their REVEAL‐SCAN participant’s amyloid PET scan result and were able to explain what the result meant. For example, they generally understood that an “elevated” result indicates an increased but uncertain risk of developing dementia caused by AD. Study partners most often described feeling relief after learning a “not elevated” result, while emotions after learning an “elevated” result included sadness, concern, and resignation. Study partners felt the amyloid PET scan result gave them additional insight into the REVEAL‐SCAN participant’s memory. Nearly all study partners denied that learning the amyloid PET scan result changed their relationship with the REVEAL‐SCAN participant, but they reported changing future plans (e.g., about leisure, caregiving) in light of the result.ConclusionStudy partners’ understanding of and reactions to another person’s amyloid PET scan result mirror those of the person. This suggests that disclosure of AD biomarkers in clinical practice will have implications not only for patients but also for their families. Looking forward, clinicians will need guidelines for how best to disclose biomarker results, including engaging and supporting patients’ family members.
Co‐designing caregiver‐centered care health workforce competencies and training: Making the leap to support family caregivers of people living with dementia
Authors: Parmar Jasneet , Poole Lisa , Anderson Sharon Dorothy , Duggleby Wendy , Holroyd‐Leduc Jayna , Brémault‐Phillips Suzette , Pollard Cheryl , Charles Lesley , Haq Anwar 
Published: December 2020

AbstractBackgroundFamily caregivers [FCGs] provide over 80% of the care for people with dementia, chronic illness and impairments. Despite evidence of their contributions and consequences of caregiving, support for FCGs has not been a health system priority. Our innovative solution to reduce caregiver distress and support caregivers to maintain their wellbeing is to educate the health workforce to identify, engage, and support family caregivers throughout the care trajectory. Education to prepare health providers to effectively identify, engage, assess, and support all FCGs is innovative approach to addressing inconsistent system of supports for FCGs. Objective: We will present the co‐design process and introduce our Health Workforce Caregiver‐Centered Care Education focused on dementia. To ensure a specific person‐centered focus on family caregivers, we created the term “caregiver‐centered care” defined as a collaborative working relationship between families and healthcare providers in supporting family caregivers in their caregiving role, decisions about services, care management, and advocacy. Project Description: We designed our Caregiver Centered Care Education using effective practices for dementia education for the health workforce. The Caregiver Centered Care Competency Framework validated in March, 2019 underpins the design and evaluation.MethodsWe engaged over 100 multi‐level, interdisciplinary stakeholders familiar with dementia care from diverse settings. We ensured that we included FCGs of people living with dementia, to co‐design Caregiver Centered Care Education for the Health Workforce.ResultsWe co‐designed dementia focused competency‐based education modules aligned with the previously validated Caregiver‐Centered Competencies for the health workforce. The teaching and learning resources include competency‐aligned educational modules, multimedia resources, and facilitators guide that are designed flexibly, to be tailored to settings and learners. Discussion: The hallmark of effective education is content relevant to learners’ needs and contexts. We will pilot test the Caregiver‐Centered Care Education, for acceptability and effectiveness, in five contexts: primary care, acute care homecare, supportive living, and long‐term care.ConclusionOur education will support caregiver‐centered care in all settings providing dementia‐related care. Health workforce support will be essential to maintaining FCG wellbeing and sustaining the family caregiving that reduces health system costs.