bluuebunny/crossref_metadata_2025_split huggingface dataset:
Life’s Simple 7 Relates to Better Cognitive and Brain Health in Individuals with Autosomal Dominant Frontotemporal Dementia
Authors: VandeBunte Anna M , Kramer Joel H. , Casaletto Kaitlin B. , Paolillo Emily W. , Saloner Rowan , Lee Hyunwoo , Hsiung Ging‐Yuek Robin , Staffaroni Adam M. , Lee Shannon Y. , Tartaglia Carmela , Heuer Hilary W. , Boeve Brad F. , Boxer Adam L. , Rosen Howard J. 
Published: December 2023

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.
Development and Comparison of a Novel Mid‐Region Directed p‐Tau 181 Assay with Tau Positron Emission Tomography in Alzheimer’s Disease
Authors: Tagai Kenji , Tatebe Harutsugu , Matsuura Sayo , Zhang Hong , Kokubo Naomi , Matsuoka Kiwamu , Endo Hironobu , Oyama Asaka , Hirata Kosei , Shinotoh Hitoshi , Kataoka Yuko , Matsumoto Hideki , Oya Masaki , Kurose Shin , Takahata Keisuke , Ichihashi Masanori , Kubota Manabu , Seki Chie , Shimada Hitoshi , Takado Yuhei , Kawamura Kazunori , Zhang Ming‐Rong , Higuchi Makoto , Tokuda Takahiko 
Published: December 2023

AbstractBackgroundSeveral blood‐based phosphorylated tau (p‐tau) assays that focus on the N‐terminus have been developed and established as non‐invasive biomarkers for detecting Alzheimer’s disease (AD) pathologies from their early stages. However, the p‐tau measured by these assays may not necessarily reflect the accumulation of tau lesions in the brain due to correlation with Aβ burden. Therefore, there remains a significant unmet need to develop blood‐based tau biomarkers that are interchangeable with tau deposits in the brain.MethodsWe have devised a novel Simoa assay that can detect N‐ and C‐terminally truncated fragment of p‐tau181 in plasma (QST assay), utilizing an antibody against the mid‐region of tau protein for capture, and an antibody AT270 for detection. The plasma p‐tau181 was measured with both the QST assay and a conventional p‐tau181 Simoa assay (Quanterix) in 164 subjects, including 40 cognitively normal (CN) individuals, 48 with AD continuum, 50 with progressive supranuclear palsy, and 26 with other frontotemporal lobar degeneration, who underwent Aβ (11C‐PiB) and tau (18F‐PM‐PBB3, Florzorotau) positron emission tomography (PET) scans. Subsequently, we conducted a head‐to‐head comparison of p‐tau181 assays in correlation with the imaging biomarker and cognitive dysfunction.ResultsQST p‐tau assay demonstrated inferior performance compared to the Quanterix assay in the qualification of Aβ PET (QST assay: AUC = 0.771, Quanterix assay: AUC = 0.867). Neither assay showed a significant correlation with Aβ PET accumulation in the AD group. Meanwhile, the QST assay exhibited excellent correlations with tau PET accumulation in regions indicative of AD including temporal cortex and neocortex (p<0.0005), whereas the Quanterix assay demonstrated non‐linear correlations with tracer binding. In trajectories from CN to AD continuum, the QST assay exhibited a linear association, as well as tau PET accumulation, while the Quanterix assay exhibited a sigmoidal curve association.ConclusionsWe have developed a new p‐tau181 assay directly correlated with tau PET accumulation. This quantitative system serves as a promising surrogate marker for tau lesions in the AD brain, which facilitate screening and monitoring of tau deposits in various settings, including developing disease‐modifying therapeutics.
Functional connectivity of the frontoparietal control network is positively associated with cognition, independent of amyloid and tau burden, in the A4 study
Authors: Boyle Rory , Shirzadi Zahra , Coughlan Gillian T , Properzi Michael J , Chhatwal Jasmeer P. , Buckley Rachel F. , Sperling Reisa A. , Schultz Aaron P. 
Published: December 2023

AbstractBackgroundThe Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study is the first secondary prevention trial of an anti‐amyloid therapy, solanezumab, in cognitively unimpaired older adults with elevated amyloid‐beta (Ab)‐PET burden. The inclusion of resting‐state functional connectivity MRI (fcMRI) as a secondary outcome measure is a novelty for clinical trials. Despite promising longitudinal findings, there is mixed evidence for cross‐sectional associations between functional connectivity in the default mode (DMN) and frontoparietal control (FPCN) networks, with Ab, tau, and cognition. Here, in a large cross‐sectional sample, we investigate these associations and assess whether fcMRI accounts for variability in cognition that is not attributable to Ab or tau.Method1,641 participants from A4 and the LEARN observational arm with fcMRI passed quality control and had complete data for sociodemographics, cognition, and Ab (Florbetapir)‐PET (Table 1). A subset had tau (Flortaucipir)‐PET (n = 420). Within‐network connectivity estimates of the default mode (DMN) and left and right frontoparietal control networks (FPCN) were obtained using template‐based rotation (Fig. 1).Using hierarchical regressions, we examined the independent associations of functional connectivity with Ab burden (mean cortical standardized uptake value [SUVr]), tau burden (mean of inferior temporal and entorhinal SUVrs), and cognition (Preclinical Alzheimer’s Cognitive Composite), independent of covariates (age, sex, education level, head motion, scanner and, where applicable, Ab and/or tau burden).ResultAb and tau burden were not independently associated with DMN or right FPCN connectivity. Higher tau was associated with reduced left FPCN connectivity, independent of Ab. Stronger left and right FPCN connectivity were associated with better cognition, independent of Ab and tau (Table 2). This association was stronger for the left FPCN.ConclusionFPCN functional connectivity is associated with better cognition, independent of Ab and tau burden. This association was strongest in the left FPCN and supports evidence that implicates FPCN connectivity in cognitive reserve and resilience. While this association is robust, weak effect sizes suggest that functional connectivity explains a limited amount of variability in cognition after accounting for covariates and AD pathology. Future release of the A4 study longitudinal data will enable quantification of the added value of fcMRI in AD clinical trials.
Enrollment and Scientific Progress of the Multisite SuperAging Research Initiative
Authors: Rogalski Emily J , Huentelman Matthew J , Roberts Angela C , McIlroy William , Van Ooteghem Karen , Finger Elizabeth , Lim Andrew , Okonkwo Ozioma , Goldstein Felicia C , Martersteck Adam , Parrish Todd , Scholtens Denise , Gill Nathan Pruneau , Tull Mary Beth , Pina Yasmin , Dorn Megan , Carolan Padraig , Zemlock Debby , Eldes Fatima , Amador Gabriella , Mather Molly A , Engelmeyer Janessa , Weintraub Sandra , Geula Changiz , Mesulam Marsel , Maher Amanda Cook 
Published: December 2023

AbstractBackgroundThe SuperAging Research Initiative is a multisite consortium focused on identifying factors promoting extraordinary cognitive aging. The designation of SuperAger is reserved for individuals age 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The presence of such outliers raises questions of fundamental importance to the neurobiology of brain aging, resilience, resistance, and avoidance of cognitive decline caused by Alzheimer’s disease. The original study of SuperAgers emerged at Northwestern and helped establish the phenotype. The SuperAging Research Initiative was established in 2021 and is focused on increasing minority representation and expanding deep phenotyping of this unique population.MethodsHarmonized data collection has been initiated across the five sites including behavioral, health, biologic, genetic, environmental, socioeconomic, psychosocial, neuroanatomic, and neuropathologic factors. Here we summarize the initial recruitment progress and baseline characteristics of the current cohort.ResultsWe will present the organizational structure, progress, and baseline characteristics of the cohort to date. The SuperAging Research Initiative includes three Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology) and two Research Projects. Enrollment (target, n = 500) has commenced across four U.S. Sites located in Illinois, Wisconsin, Michigan, and Georgia, and a Canadian Site in Southwest Ontario, with a focus on enrollment of Black SuperAgers and Cognitively Average Elderly Controls with similar demographics. Project 1 uses state‐of‐the‐art wearable technology to obtain quantitative measurements of daily life including, sleep, physical activity, autonomic responsivity, and social engagement to determine whether SuperAgers have relatively preserved physiologic and behavioral ‘complexity’ compared to Controls. Project 2 focuses on transcriptomic, genetic, and protein profiling to examine central and peripheral immune and inflammatory system parameters of SuperAgers.ConclusionsBy identifying factors contributing to superior memory performance in old age, outcomes may help isolate modifiable factors that promote healthspan and perhaps also prevent age‐related brain diseases such as Alzheimer’s disease.
Familial relatedness in genetic frontotemporal dementia cohorts: findings from the international Frontotemporal Dementia Prevention Initiative
Authors: Ramos Eliana Marisa , Mirza Saira S. , Wojta Kevin , Yang Zhongan , Paterson Andrew D. , Rogaeva Ekaterina , Brushaber Danielle , Foroud Tatiana M. , Forsberg Leah K. , Heuer Hilary W. , Russell Lucy L. , Lago Argentina Lario , Rademakers Rosa , Boeve Brad F. , Rosen Howard J. , Rohrer Jonathan D. , Boxer Adam L. , Masellis Mario , Geschwind Daniel H. ,   GENFI and ALLFTD consortia
Published: December 2023

AbstractBackgroundGiven the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large‐scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses.MethodsGenome‐wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy‐Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two‐stage approach, to calculate pairwise identity‐by‐descent (IBD) estimates and KING coefficients, followed by family‐network identification and pedigree reconstruction using PRIMUS.ResultsFirst, we calculated IBD estimates among all participants by restricting pairs to those with estimates>0.1875 (up to second‐degree relatives). Overall, we identified a total of 292 second‐degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD‐causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi‐site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry‐based analysis among participants with estimated European ancestry, using the KING‐robust algorithm.ConclusionsThese lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies.
Causal Associations Between Plasma Protein Levels and Alzheimer Disease
Authors: Guen Yann Le , Belloy Michael E , Kasireddy Nandita , He Zihuai , Greicius Michael D 
Published: December 2023

AbstractBackgroundThe aim of this study was to infer causal relationships between protein levels measured in blood and the risk of late‐onset Alzheimer disease (AD).MethodTwo‐sample Mendelian randomization (MR) was used to infer the causal effect of protein levels on AD risk. Summary statistics from genome‐wide association studies (GWAS) for 4,907 SomaScan aptamers (measuring 4,719 proteins) from Ferkingstad et al. (2021) in 35,559 Icelanders (average age = 55±17years), and for AD GWAS from Bellenguez et al. (2022). Instruments for exposures were selected at p < 5×10−8 and p < 5×10−6 thresholds respectively for the main and sensitivity analyses. Instruments were pruned for linkage disequilibrium (r2 < 0.0001) to ensure selection of independent instruments. Because APOE is highly pleiotropic and exposure effect size is hypothesized by MR not to be larger than the outcome (Steiger filtering), thus variants within ±1MB from APOE were removed in the MR‐analysis. Two tests were considered: Inverse‐Variance‐Weighted and Weighted‐Median, which allows robust MR estimates even when some invalid instruments are included.ResultAmong known AD‐GWAS genes, TREM2, PILRA, ACE, CR1, and BIN1 protein levels were associated with AD. Proteins without prior AD‐GWAS links were also found to be associated with AD including: PPBP, NRP2, AZGP2, and TNFSF13B/BAFF (Figures 1&2). Interestingly, APOE and KLOTHO levels were not associated with AD (Figures 3&4), though increased APOE level significantly associated with increase AD risk when including cis‐APOE variants at p < 5×10−6 (Figure 5).ConclusionOur study informs the directionality of association between certain plasma protein levels and AD risk, and prioritizes candidate proteins to be considered for AD drug development.
Contactless fall detection with radio frequency sensors for the aging population
Authors: Khan Arshia A , Johnson Brian B , Snyder Kristine 
Published: December 2023

AbstractBackgroundFalls remain a primary concern for People with Dementia (PwD) living in long‐term care facilities (LTCFs) despite many prevention and intervention methods that have tried. Current fall detection monitoring systems use wearable or vision‐based sensors. The problem is research has shown that many seniors will not consistently wear a device on their body or allow cameras in their living space because of privacy concerns that severely limit the technology user acceptance. The current standard of care is self‐report or eyewitness and therefore fall events are often undetected and underreported due to human error. Hence, we are proposing a solution to address this unmet need with a novel fall management system engineered with radio frequency (RF) sensors that do not require an individual to wear or interact with a device.MethodSix healthy participants simulated three types of falls, medial and lateral, anterior and posterior, and collapse in the Dementia and Elderly Care Robotics and Sensing (DECRS) Lab, University of Minnesota Duluth. The sensor was installed in the lab as it would be in the resident room of an LCTF. The simulated room included a bed, chair, and mattress on the floor to protect the participants.ResultOur study found that the contactless fall detection and activity system identified falls at overall sensitivity rate of 89% with a specificity of 100% in 748 tests and activity was identified at 90%. Our system identified “medial and lateral” falls with a 92% sensitivity, “anterior and posterior” falls with a 91% sensitivity, and “collapse” falls with a 75% sensitivity.ConclusionContactless sensing holds tremendous potential for monitoring individuals living with AD/ADRD and the elderly population for aging in place. LTCFs that are short staffed could benefit by utilizing tools that augment the capabilities of nurses with a continuous collection of patient‐generated health data (PGHD) and a notification system that is integrated with existing workflows and only send alerts for potential events that would require immediate attention.
Humanoid Mobile Robots and wearable sensors improve the quality of care and address worker shortages in nursing homes
Authors: Khan Arshia A 
Published: December 2023

AbstractBackgroundTechnology has been identified as a solution to address the growing healthcare worker shortages(Harp, 2023). Humanoid robots have great potential to help augment care in elderly and people affected with dementia (Khan & Anwar, 2020; Joseph et.al, 2018).Humanoid robots and wearable sensors were deployed in eight nursing homes to help address healthcare worker shortages and augment care of elderly and people affected with dementia. The resident satisfaction and quality of life annual survey conducted by the Minnesota Department of Human Services revealed an improved satisfaction and quality of life in the domain of activities in the nursing homes that deployed robots when compared to the nursing homes that did not deploy the robots. The pre and post data gathered revealed that the residents felt happier, more cared for, less tired and less frustrated after interacting with the robots. The staff feedback indicates that the staff had time to address their chores while the robots engaged teh residents.MethodTwo humanoid robots and ten wearable sensors per facility were deployed in 8 different nursing homes. The robots were programmed to address the domains of physical, emotional/social and cognitive wellbeing. Four forms of data ‐ 1) nursing home resident satisfaction and quality of life data gathered by the Minnesota Department of Human Services; 2) pre and post surveys conducted before and after interactions with the robots; 3) weekly feedback was from the healthcare staff and wearable sensor data.ResultThe nursing home resident satisfaction and quality of life data gathered annually by the Minnesota Department of Human Services revealed improvement in the satisfaction and the quality of life domain of activities in the nursing homes that deployed humanoid robots versus the nursing homes that did not deploy humanoid robots. The pre and post surveys conducted before and after the interactions with the robots showed 17.4% improvement in their happiness, 4.3% more cared for,10% less tired and 14.5% less frustrated after engaging in the activities with humanoid robots.ConclusionHumanoid robots and wearable sensors have proved to help improve the quality of life of elderly.
Amyloid‐dependent tau phosphorylation drives faster accumulation of tau aggregates in female
Authors: Wang Yi‐Ting , Therriault Joseph , Servaes Stijn , Tissot Cécile , Rahmouni Nesrine , Arias Jaime Fernandez , Benedet Andrea Lessa , Mathotaarachchi Sulantha , Stevenson Jenna , Ashton Nicholas J. , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundThe high prevalence of Alzheimer’s dementia in females have long puzzled researchers in the field. Despite similar amyloid levels, females show higher load of neurofibrillary tangles (NFTs). Previous literature proposed that amyloid‐β (Aβ) and phosphorylated tau (p‐tau) synergism accelerates biomarker abnormalities. However, it remains to be answered whether this synergism is the driving force behind faster tau progression in females. The overarching goal of the study wa to investigate whether amyloid‐β aggregates differentially impose tau hyperphosphorylation and neurofibrillary tangles formation in a sex‐specific manner.MethodIn this longitudinal study, we assessed 287 participants from TRIAD cohort at McGill University Research Centre for Studies in Aging. Cerebral Aβ and tau deposition were assessed with positron emission tomography (PET) radiotracers [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240, respectively. Cerebrospinal fluid (CSF) p‐tau181 and p‐tau217 were also measured (analysed at the Clinical Neurochemistry Laboratory at the University of Gothenburg, Sweden). Regression and voxel‐based models with interaction terms were used to evaluate baseline tau load and NFT accumulation rate as a function of sex and baseline biomarkers (Aβ and p‐tau).ResultWe identified sex difference in the relationships between CSF p‐tau, Aβ and NFT (Fig 1). Specifically, voxelwise analyses demonstrated that female presented stronger positive correlations between CSF p‐tau and AD core biomarkers (Aβ and NFT). Furthermore, we discovered that Aβ and CSF ptau181 interactively potentiated tau accumulation in females but not males (Fig 2, Table 1). Together, the present results support that Aβ load imposes higher tau aggregation in females.ConclusionAβ‐dependent tau phosphorylation was the key driver for faster NFT accumulation observed in female.