bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and characterization of novel anti‐tau antibodies that inhibit tau‐seed mediated pathology in a P301S tauopathy mouse model Alzheimer’s Disease and tauopathies
Authors: Liu Wencheng , Kurella Vinodh , Liu Li , Kavanagh Dillon , Paranjpe Maneesha , Holth Jerrah , Chung Charlotte , Powers Alex , Ren Xiao‐Qin , Shu Yanqun , Capili Allen , Hou Jay , Ghetti Bernardino Francesco , Bales Kelly R. , Paul Steven M. , Carter Todd 
Published: December 2022

AbstractBackgroundThe current hypothesis for the progression of tau pathology in Alzheimer’s disease (AD) and tauopathies (for example, Progressive supranuclear palsy (PSP)), is based on mechanisms involving seeding and propagation of pathologic tau via cell‐to‐cell transmission, including trans‐synaptic propagation, a mechanism which provides the opportunity for anti‐tau immunotherapy as a logical and promising therapy for these diseases.MethodWe have carried out parallel immunization campaigns with various immunogens and host animals aimed to isolate a diverse starting pool of anti‐tau antibodies. Immunization of mice with AD patient‐derived PHF‐tau (paired helical filamentous tau) as the immunogen yielded 113 hits demonstrating significant binding to PHF‐tau and an absence of binding to wild type recombinant tau.ResultHere, we describe the characterization of these 113 anti‐tau antibodies based on their biochemical and biophysical properties, including affinity for PHF‐tau, immunohistochemical selectivity for AD/PSP in human brain sections, functional inhibition of PHF seeding in vitro, developability, as well as epitope mapping. 10 antibodies that met the target profile described above were selected for in vivo efficacy screening in the P301S seeding‐propagation tauopathy mouse model. Epitope mapping for these 10 antibodies demonstrates that these antibodies target phospho‐tau epitopes in diverse locations throughout the tau protein, with six antibodies targeting the mid‐domain region, three targeting the C‐terminal region, and one targeting the N‐terminal/mid‐domain region. We have evaluated five antibodies for their ability to block PHF seeding/propagation in a P301S mouse seeding model and demonstrated substantial reduction of induced tau pathology. Five additional antibodies are currently under evaluationConclusionIn summary, we have generated a set of potent and specific anti‐tau antibodies targeting a diverse set of phospho‐tau epitopes that are candidates for the treatment of Alzheimer’s disease and/or other tauopathies. Both the in vitro and in vivo data on this series of tau‐specific antibodies will be presented.
Association of Spousal Separation and Widowhood with Incident Dementia: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study (NCS)
Authors: Xie Jiaxin , Pike James R. , Walker Keenan A , Sullivan Kevin J , Windham B Gwen , Gottesman Rebecca F 
Published: December 2022

AbstractBackgroundCommunity‐based investigations suggest that being unmarried in mid‐ to late‐life increases dementia risk. However, these studies rarely distinguish the cause of unmarried status (i.e., whether divorced, widowed, or never married). We prospectively examined spousal separation/loss and dementia incidence in the ARIC study.Method14,922 participants reported marital status and were dementia‐free at baseline (Visit 3, 1993‐95; mean age 59.6, SD 5.8). They were followed through 2019 with annual follow‐up surveys of marital status (never married [n = 390], married [n = 7,314], divorced/separated [n = 1,512], widowed [n = 5,706]). Widowed or divorced/separated participants were asked when this event occurred. Dementia cases were adjudicated through in‐person evaluations, informant interviews, and phone assessments from Visit 5 onward, and pre‐ and post‐Visit 5 hospitalization codes and death certificates. We investigated the association between being widowed and being divorced/separated (both as time‐varying variables) with dementia (excluding dementia in the first year after widowhood event) using Cox proportional hazards models, adjusted for demographics, APOEε4, and vascular risk factors.Results2,931 dementia cases were identified. Demographic‐ and APOEε4‐adjusted hazard ratio (HR) (95% CI) for dementia was 1.11 (1.02‐1.21) in participants who were widowed compared to those who were not widowed, when time‐varying widowhood status was considered. (Table 1). This association was no longer significant when the model was further adjusted for time‐variant covariates (e.g., vascular risk factors, occupation, health insurance status). A similar pattern was seen for number of times widowed, where results were suggestive of elevated dementia risk in minimally adjusted but not more fully adjusted models. Compared to participants who were neither widowed nor separated, participants who were widowed had a higher unadjusted HR (95% CI) for dementia, HR = 1.78 (1.65‐1.93) vs HR = 0.94 for those who were separated or divorced (0.81‐1.09) (Table 2).ConclusionWidowhood is associated with dementia incidence in minimally adjusted models, with limited evidence that the association is stronger than that which is seen from divorce/separation alone. However, this association was not statistically significant in the adjusted model, indicating that other factors may contribute to the observed relationship.
The effects of outdoor versus indoor exercise on psychological health, physical health, and exercise behaviour: a systematic review of longitudinal trials
Authors: Noseworthy Matt W , Peddie Luke , Buckler Elizabeth Jean , Park Faith , Pham Margaret , Pratt Spencer , Singh Arpreet , Liu‐Ambrose Teresa , Puterman Eli 
Published: December 2022

AbstractBackgroundA growing body of research is exploring the potential added health benefits of exercise when it is performed outdoors in nature, as compared with indoors. We systematically reviewed longitudinal trials comparing the effects of exercise in outdoor versus indoor environments on psychological and physical health, and exercise behaviour.MethodsWe searched the following nine databases from inception to March 2021 for English‐language, peer‐reviewed articles: MEDLINE, Embase, PubMed, Scopus, Web of Science, CINAHL, SportsDiscus, GreenFile, CENTRAL. We included randomized and non‐randomized trials that compared multiple bouts of exercise in outdoor versus indoor environments, and that assessed at least one of the following main outcomes of interest: physical health, psychological health, or exercise behaviour. We assessed risk of bias using the Revised Cochrane risk‐of‐bias tool for randomized trials. At least two authors screened articles for eligibility, extracted data, and evaluated risk of bias, with discrepancies resolved by discussion with at least one other author. Due to outcome heterogeneity and a paucity of studies, we performed a narrative synthesis.ResultsWe identified 10 eligible trials from 12 papers, including seven randomized controlled trials. Participants’ (n = 496 total) demographics varied widely (mean age ranging from 11‐80 years). Most exercise protocols involved 30‐60 minutes of aerobic training (walking or running) at moderate to high intensity. Other forms of training included mixed aerobic and resistance training, agility, balance, and strength training, and dual‐task training. Exercise sessions took place one to 5 times per week for one to 18 weeks. Outcomes overlapped minimally between trials, with psychological outcomes assessed in seven trials, physical outcomes assessed in eight trials, and behavioural outcomes assessed in three trials. In total, 123 comparisons were made between outdoor and indoor exercise, including 33 significant comparisons, all of which favoured outdoor exercise. Interpretation of findings was hindered by an overall high risk of bias, unclear reporting, and high heterogeneity in reported outcomes.ConclusionThere is limited evidence for added health or behaviour benefits of chronic exercise in outdoor environments, as compared with indoors, and a need for future, high‐quality longitudinal trials with adequate power and clear reporting.
Nurr1 and Foxa2 Delivered by Adeno‐Associated Virus 9 Ameliorate the Pathologies and Symptoms of Alzheimer’s Disease Models
Authors: Lee Sang‐Hun , Lee Seong Hoon , Kim Tae‐Gyun 
Published: December 2022

AbstractBackgroundSince conventional chemical drugs or proteins have not shown sufficient clinical benefits for cognitive impairments in Alzheimer’s disease (AD), we could try to develop novel therapeutic interventions for AD such as gene therapy. In this study, we evaluated a novel therapeutic modality of AAV9 vectors expressing Nurr1 and Foxa2 genes to treat AD symptoms and pathologies in animal disease models.MethodThe AAV9 vectors expression Nurr1 and Foxa2 were injected together into the hippocampi and lateral ventricles of two different AD models, such as 3x Transgenic (15‐18 months) and 5x Familial Alzheimer Disease (3 months) mice. We tested memory and cognitive functions, accumulation of amyloid β and Tau protein, inflammation and immune activity in the brain of AD models.ResultCombined transduction of AAV9‐Nurr1 and AAV9‐Foxa2 remarkably improved memory and cognitive functions of 3xTg mice in Y‐maze and water‐maze tests compared to vehicle‐treated group. In 5xFAD mice, Nurr1 and Foxa2 co‐expression effectively rescued memory deficits in the passive avoidance and novel object recognition tests, and made the impaired long‐term potentiation restore to wild‐type level.We intensively investigated modes of action of therapeutic genes. Nurr1 and Foxa2 co‐expression significantly decreased Aβ deposits in the brain of 3xTg and 5xFAD mice. Subsequent transcriptome analyses revealed that two genes up‐regulated the expression of Aβ‐degrading enzymes.Tau plaque formation was also reduced in therapeutic gene‐treated 3xTg group, accompanied by deceased phosphorylation of Tau through inflammasome suppression and GSK‐3β inactivation.Nurr1 and Foxa2 ameliorated neuro‐toxic environment by correcting pathologic inflammatory glial phenotypes. They decreased the expression of inflammatory cytokines, chemokines, and complements through inactivation of NF‐κB pathway, while up‐regulated expression of neurotrophic factors.Along with increased expression of pre‐ and post‐synaptic markers, synaptic density in the hippocampal CA1 was greater in the 3xTg mice treated with therapeutic genes than control.ConclusionA series of functional, histologic and transcriptome analyses revealed that the co‐expression of Nurr1 and Foxa2 attenuated AD‐associated Aβ and Tau proteinopathy, neuro‐inflammation, immune activation, and synaptic loss in multiple in vitro and in vivo AD models. These findings collectively indicate intra‐cranial delivery of Nurr1 and Foxa2 using AAV9 could be an efficient disease‐modifying therapy for AD.
Clinical significance of physical frailty in SCD subjects: A prospective study with amyloid PET data
Authors: Lim Eun Ye , Yang Dong Won , CHO Ahyun , Ho SeongHee 
Published: December 2022

AbstractBackgroundPhysical frailty is known to be closely associated with cognitive impairment and that it could be an early sign of Alzheimer disease (AD). We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in SCD subjects with amyloid data.MethodWe prospectively enrolled SCD subjects from of cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from subjective cognitive decline (CoSCo) study. They all went through brain magnetic resonance imaging (MRI), and Florbetaben brain amyloid‐beta Positron Emission Tomography (PET). For physical frailty, self‐reported exhaustion, hand grip strength and gait speed were measured.ResultOf total 120 SCD subjects, 26 (21.7%) subjects showed positivity in amyloid PET scan. Logistic regression analyses showed that women (OR 3.79, p = 0.002) and amyloid PET positive (OR 3.80, p = 0.008) SCD subjects showed significantly more self‐reported exhaustion. Weak hand grip strength was significantly associated with Amyloid PET positivity (OR 3.22, p = 0.047) and high burden of periventricular WMH (OR 3.34, p = 0.023). The SCD subjects with physical frailty showed lower cognitive performance in neuropsychological test, especially information‐processing speed and executive function.ConclusionThe components of physical frailty are closely related to amyloid and cerebral vascular pathology in SCD subjects and the SCD subjects with physical frailty showed lower cognitive performance in neuro‐psychological test, especially information‐processing speed and executive function.
Prevalence, incidence and associations of dementia with cardiovascular risk factors in the Latin American and Caribbean population. A population‐based cohort study of 10/66 Dementia Research Group
Authors: Llibre‐Rodriguez Juan J. , Acosta Daisy M , Llibre‐Guerra Jorge J , Guerra Mariella , Velazquez Ivonne Z. Jimenez , Salas Aquiles , Ortiz Ana Luisa Sosa , Prince Martin J 
Published: December 2022

AbstractBackgroundLatin America and the Caribbean (LAC) countries are experiencing unprecedentedly rapid demographic ageing. Growing evidence shows that cardiovascular health (CVH) is associated with brain health. Little is known about this topic among older adults in Latin America, where the number of people living with dementia is rising. The present study aimed to examine the prevalence, incidence and associations of socioeconomic determinants and cardiovascular risk factors with dementia across six LAC countries.MethodsThe 10/66 Dementia Research Group has carried out population‐based catchment area surveys, using a common protocol, in six Latin‐American countries Cuba, Dominican Republic, Mexico, Peru, Puerto Rico and Venezuela of all over 65 year old (n = 12 704). An incidence wave was conducted 4 ‐5 years after cohort inception, 8 502 participants were reinter viewed, contributing 34 000 person‐years of follow‐up. The outcomes were 10/66 dementia and DSM IV dementia. An index of modifiable CVH factors (ranging from 0 to 14) was calculated. Incident dementia was modeled using competing risks regression to adjust for risk of death.ResultsThe prevalence of dementia varied widely across different countries, ranging from 4.8% in Peru and 11.7% in Puerto Rico and the Dominican Republic. Incidence of 10/66 dementia varied between 18.2 (95% CI 14.3‐23.0) per 1000 person‐years in Peru to 30.4 (25.5‐36.3) per 1000 person‐years in Mexico. Being male, having higher education and younger age were all protective of dementia. Specific cognitive tests including literacy, verbal fluency and motor sequencing had also similar protective associations with dementia, providing more supporting evidence for the cognitive reserve hypothesis. Compared to poor CVH, participants with moderate and ideal levels of CVH had a significantly lower risk of dementia both in the unadjusted (subhazard ratio for moderate: 0.77; ideal: 0.59) and adjusted models (moderate: 0.73; ideal: 0.66).ConclusionsThe prevalence of dementia in the older Latin American and Caribbean population is high. Moderate and ideal levels of CVH in old age may protect against dementia incidence. These findings may inform health promotion efforts within dementia national plans adopted recently in some Latin American countries
Characterization of Tau vaccines identifies diverse antibody binding profiles and efficacy, demonstrating that specific forms of Tau can be targeted by vaccines with subsequent functional impact.
Authors: Boyd Justin 
Published: December 2022

AbstractBackgroundImmunotherapy has become a tractable path for Alzheimer’s disease therapies. One of the impediments of these therapies is their intrinsic limitation of targeting, particularly regarding Tau. It is unclear to what degree these therapies target the specific disease‐causing Tau form in each individual patient at the required time in disease progression. To address these challenges, Vaxxinity is developing a vaccine derived immunotherapy targeting Tau.MethodVaccines were designed by selecting various peptide sequences along the Tau protein, conjugating to Vaxxinity’s UBTh1 peptide and formulating with CpG and Adju‐Phos. Immunogenicity of vaccines were quantified in guinea pigs and mice by ELISA. Vaccine derived antibodies were characterized by Western Blot, dot blot, immunohistochemistry and Bio‐Layer Interfereometry. Vaccine efficacy was characterized by examining the effects of vaccine derived antibodies with in vitro assays (Tau aggregation and spreading) and quantifying Tau accumulation in the brains of vaccinated mice.ResultVaccines induced robust immunogenicity with high titers. Antibodies derived from vaccines exhibited diverse binding profiles, including the production of antibodies binding preferential Tau species and those appearing to bind total Tau. Efficacy was also observed within the in vitro assays, including reduction of Tau aggregation and spreading. Modest reduction of Tau accumulation was observed in mice, with more analysis pending.ConclusionHere we present early‐stage data illustrating that the Vaxxinity platform can target a range of Tau forms in a single vaccine. Animals vaccinated with a vaccine targeting Tau produce robust antibodies against a range of Tau forms (monomeric, oligomeric and fibrils), exhibiting high titers, selectivity, and avidity. Moreover, efficacy data from animal models support the potential for future efficacy in humans.
Predictors of Alzheimer’s disease risk in women with bilateral oophorectomy from the UK Biobank
Authors: Reuben Rebekah , McFall G. Peggy , Dixon Roger A. , Einstein Gillian 
Published: December 2022

AbstractBackgroundTwo‐thirds of individuals with Alzheimer’s disease (AD) are women and at age 45, the lifetime risk for AD is twice as high in women compared to men (Alzheimer’s Association, 2019). Early life events affecting 17β‐estradiol (E2) may be a mechanism behind this sex difference. Bilateral oophorectomy (BO) predicts cognitive decline, and neurodegeneration, and increased risk of AD in later life—adverse outcomes that are mitigated with E2 therapy (Gervais et al., 2020; Kantarci et al., 2018; Rocca et al., 2007; Zeydan et al., 2019). Our aim was to investigate compounding risk factors for AD in women with BO using UK Biobank data.MethodWe studied women aged 60 or older who had BO prior to age 49 with an AD diagnosis (n = 53) and without an AD diagnosis (n = 5418) from the UK Biobank (Sudlow et al. 2015). Data were analyzed using Firth’s bias‐reduced logistic regression in R 3.6.1 (R Core Team, 2019).ResultParticipants were on average 63.7 years old and 43.4 years old at BO. Women with BO who developed AD: (a) were significantly older, (b) had fewer years of education, (c) had an earlier age at BO, (d) less frequently used any form of hormone therapy (HT), and (e) were more frequently apolipoprotein E4 (APOE4) carriers. As age increased, AD risk increased by 25%; it deceased by 10% with greater years of education. Women with BO and an APOE4 allele were 5.2 times as likely to develop AD than those without an APOE4 allele. Finally, ever using any form of HT decreased AD risk by 54%.ConclusionThis research fills a gap in understanding predictors of AD in a high‐risk group of women with early E2 loss. The heightened AD risk for women with BO and APOE4 is of note, as prior work suggests women with APOE4 may benefit less from HT (MacLusky, 2004). Further, the reduction in AD risk with any HT provides added support for HT in mitigating cognitive decline. Although details on HT formulation were unavailable, the specific use of E2‐based therapy may further decrease AD risk (Sherwin & Henry, 2008).
Validating a set of Verbal‐Paired‐Associates word‐pair lists for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K 
Published: December 2022

AbstractBackgroundVerbal‐Paired Associates (VPA) is a widely used memory task, typically administered by a trained rater, with lists of pairs of words learned over up to three attempts, followed by delayed recall. Automated scoring and administration could enable remote testing to monitor change over time but requires parallel forms of the test with equivalent psychometric properties. Here we describe the validation process and memorability characteristics of a group of 12 parallel forms of automated VPA.MethodWe generated 15 candidate VPA word‐pair lists based on prior modelling. Piloting and simulation‐based power calculations suggested a sample size of 375 would provide power of .8 to detect lists where the mean number of errors at the first attempt was more than one error different from the Grand Mean. We recruited 375 healthy participants aged 50‐90 years via the Prolific online platform. We used a mixed counterbalanced design with the aim of evaluating the memorability characteristics of the candidate set of word‐pair lists. Participants were tested twice on the VPA task using different word‐pair lists, separated by a distractor task. All testing was delivered via the NeuroVocalix platform on participants’ own devices at home and was administered and scored automatically using automatic speech recognition. Automated scoring results were reviewed by a human experimenter to ensure accuracy.ResultMemory performance in individual word‐lists conformed broadly to our model‐based expectations, with significant correlations between predicted and observed performance (p < 0.05). We observed expected significant improvement in recall performance with repeated administration, showing learning of word pairs over the task. In this healthy sample there was only modest forgetting at delayed recall. Although performance was broadly equivalent across the different lists, the final selection of lists excluded three with the highest numeric difference in performance versus the overall grand mean, yielding 12 lists for repeated administration. Qualitative feedback showed good levels of acceptability and engagement with the task by participants.ConclusionWe now have a set of 12 parallel‐form word‐pair lists for use with the automated NeuroVocalix system, with consistent performance characteristics enabling long‐term repeat testing remotely and at scale.