bluuebunny/crossref_metadata_2025_split huggingface dataset:
A biological age biomarker based on circadian rest‐activity rhythms and risk of dementia
Authors: Li Peng , Gao Lei , Sun Haoqi , Gao Chenlu , Cai Ruixue , Rutter Martin K , Hu Kun 
Published: December 2023

AbstractBackgroundCircadian function is altered with aging, leading to changes in the ∼24‐h rhythms of behavior and physiology. Based on circadian rest‐activity rhythms (CRAR), we previously constructed a biological age biomarker to characterize the aging profile of circadian function—circadian age (CircAge)—in older adults (>65 years) and showed its association with risk of Alzheimer’s dementia. Here, we constructed CircAge in middle‐to‐older‐aged adults and tested whether it predicts all‐cause dementia.MethodParticipants from the UK Biobank with valid actigraphy data were studied (n = ∼97,000; 42‐78 years old). We developed a machine‐learning‐based regression model with 23 CRAR features derived from actigraphy (using cosinor, nonparametric, uniform‐phase‐empirical‐mode‐decomposition, and detrended‐fluctuation analyses). The fitting target was chronological age (ChrAge), and the prediction output was defined as CircAge. Model parameters were optimized using cross validation on 47,234 participants not performing shift work and without mental/behavioral or nervous system diseases. The optimized model was applied to all dementia‐free participants with valid CRAR (n = 80,805) to obtain their CircAge.ResultCircAge was 1.03±0.01 years older per one‐year older in ChrAge that explained ∼25% of the variance of CircAge (p<0.0001). Male sex, European ethnicity, or having mental/behavioral/nervous system diseases were associated with a greater CircAge (all p<0.0001). We compared CircAge of current shift workers (n = 6,389) with that of matched non‐shift workers to examine whether CircAge captures CRAR perturbations and found that CircAge of current shift workers was 1.1±0.2 years greater (p<0.0001) than non‐shift workers. We then associated the difference between CircAge and ChrAge (DCC, = CircAge‐ChrAge) to incident all‐cause dementia using a Cox proportional hazards model adjusting for ChrAge, sex, ethnic groups, mental/behavioral diseases, and nervous system diseases. Results showed that greater DCC predicted higher adjusted risk of all‐cause dementia (n = 451): each decade higher DCC corresponding to a 1.10‐fold higher risk (95% CI: 1.02‐1.18; p = 0.009).ConclusionCRAR patterns can be translated into a biological aging biomarker for circadian function (CircAge), and greater CircAge than ChrAge is independently associated with risk of dementia in middle‐to‐older‐aged adults. Future studies are warranted to examine the use of CircAge (and/or in combination with other risk markers) for identifying at‐risk individuals in a clinical setting.
Artificial intelligence reveals brain aging patterns in 27,402 individuals without diagnosed cognitive impairment that are linked to genetics, biomedical measures, and cognitive decline
Authors: Skampardoni Ioanna , Nasrallah Ilya M. , Wen Junhao , Cui Yuhan , Abdulkadir Ahmed , Yang Zhijian , Erus Guray , Mamourian Elizabeth , Singh Ashish , Shou Haochang , Shen Li , Nikita Konstantina , Davatzikos Christos ,   iSTAGING consortium
Published: December 2023

AbstractBackgroundUnderstanding heterogeneity of structural brain changes in aging may provide insights into susceptibility to neurodegenerative diseases. We characterize the genetics underlying brain structural heterogeneity within cognitively unimpaired (CU) individuals using data‐driven machine learning applied to a diverse dataset of 27,402 individuals from 11 neuroimaging studies from the iSTAGING consortium.MethodStructural brain morphologic patterns of CU individuals were independently examined in four decade‐long intervals spanning ages 45 to 85. Within each interval, Smile‐GAN (Yang et al., 2021) was trained on baseline anatomic and white matter hyperintensity (WMH) volumes. Smile‐GAN probability scores were used as phenotypes in genome‐wide association studies (GWAS). Specifically, we performed multiple linear regressions controlling for confounders (e.g., age) via Plink (Purcell et al., 2007). We observed longitudinal clustering stability across decades, so individuals from adjacent age groups were combined into broader age groups ([45,65), [65,85)) due to the large sample requirement of GWAS. Genomic loci, represented by the top leading single nucleotide polymorphisms (SNPs), were defined considering linkage disequilibrium. We investigated associations of SNPs with clinical traits and mapped them to genes using the GWAS Catalog (Buniello et al., 2019).ResultThree structural brain aging patterns, relative to resilient agers (A0), consistent across decades, emerged: A1, or ‘typical’ aging with low atrophy and WMHs, and two ‘advanced’ aging patterns, one showing elevated WMHs and modest atrophy (A2) and the other displaying severe, widespread atrophy and moderate WMH load (A3) (Figure 1). GWAS discovered eight and six genomic loci in [45,65) and [65,85) age groups, respectively (Table 1, Figure 2). The lead SNPs for A1 and A2 were previously associated with several cardiometabolic risk factors, WMHs, and regional brain volumes. Interestingly, rs4843552, previously associated with white matter microstructure and regional brain volumes, showed opposite effects for A1 (protection) and A2 (risk), consistent with the neuroimaging patterns. WDR41 in A3 group was previously associated with the age of Alzheimer’s disease onset (Herold et al., 2016).ConclusionReproducible neuroimaging patterns defined by regional atrophy and WMH burden were identified across CU individuals and demonstrated unique genetics. Further research is needed to elucidate the neuropathological pathways that mediate these relationships.
Biofluid phospho‐tau with subthreshold tau‐PET predicts higher rates of tau accumulation: implications for secondary prevention trials
Authors: Groot Colin , Smith Ruben , Stomrud Erik , Binette Alexa Pichet , Leuzy Antoine , Wuestefeld Anika , Wisse Laura EM , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Janelidze Shorena , Strandberg Olof , Ossenkoppele Rik , Hansson Oskar 
Published: December 2023

AbstractBackgroundAn important end‐point for disease‐modifying treatments is to target the accumulation of tau. This highlights the need to determine which individuals are most likely to accumulate tau in the future. Different biomarkers of tau become abnormal at different stages of Alzheimer’s disease and capturing the evolution of tau pathology in its entirety will rely on multi‐modal assessments. Here, we examine longitudinal changes in tau accumulation associated with elevated CSF p‐tau and tau‐PET biomarkers.MethodA total of 231 amyloid‐positive (A+) individuals from the BioFINDER‐2 study were categorised into groups based on cut‐offs for abnormal CSF p‐tau217 (P) and [18F]RO948 tau‐PET (T), yielding groups of tau‐concordant‐negative (A+P‐T‐;n = 30), tau‐discordant (A+P+T‐;n = 48) and tau‐concordant‐positive (A+P+T+;n = 18) individuals. In addition, 135 amyloid‐β‐negative, unimpaired individuals served as controls. Differences in regional tau‐PET between groups were assessed using general‐linear models, adjusted for age, sex, clinical‐diagnosis and (for cognitive measures) education. We additionally assessed the effects on cortical thickness and cognition. Mean follow‐up time was ∼2 years.ResultIn the A+P+T‐ group, even though below the threshold for positivity, tau‐PET was higher at baseline than in the control and A+P‐T‐ groups, while cortical thickness and cognition were not different between these groups. For the A+P+T+ group, tau‐PET was higher, and cortical thickness, and cognition were lower at baseline than for controls, A+P‐T‐ and A+P+T‐. Longitudinal increase in tau‐PET was faster in the A+P+T‐ group than in controls and A+P‐T‐, primarily in the medial‐temporal lobe. The A+P+T+ group showed a faster rate of tau‐PET compared to controls and A+P‐T‐ (across the entire brain), and compared to A+P+T‐ (primarily neocortex). There were no differences in cortical thinning or cognitive decline between controls, A+P+T‐ and A+P‐T‐. The A+P+T+ group showed faster cortical thinning and cognitive decline compared to controls, A+P‐T‐ and A+P+T‐.ConclusionThe A+P+T‐ group only shows tau accumulation and no cortical thinning or cognitive decline, and therefore represents an interesting population for early intervention in the AD pathological process, preventing downstream effects. The A+P+T+ group shows fast and widespread tau accumulation and will, therefore, show the greatest beneficial effect of tau‐targeted treatment but already shows cortical thinning and cognitive decline at baseline.
The role of Neuroimaging in Patient Selection and Safety Monitoring during Lecanemab Treatment
Authors: Apostolova Liana G. 
Published: December 2023

AbstractBackgroundLecanemab (Leqembi) is a monoclonal antibody therapy approved in the United States for the treatment of Alzheimer’s disease (AD). Administration of lecanemab in community settings will be guided by the appropriate use recommendations (AURs) that are soon to be published.MethodThe lecanemab AUR’s use clinical trial data as well as evidence from research and clinical practice regarding AD to inform clinicians how to administer lecanemab with optimal safety and opportunity for efficacy. Neuroimaging will play a significant role in selecting the appropriate patients for administration of lecanemab as well as in safety monitoring for adverse events such as amyloid related imaging abnormalities (ARIA). In this presentation we will review the selection and monitoring guidelines for lecanemab as detailed in the AURs.ResultMost ARIA are asymptomatic, but a few cases are serious or fatal. While micro‐ and macrohemorrhages are rare, they can occur in patients receiving lecanemab. Patients who are apolipoprotein E4 (APOE4) gene carriers, and especially those that are APOE4 homozygotes, are at higher risk for ARIA than APOE4 non‐carriers. The AURs recommends genotyping to better inform risk discussions with patients who are candidates for lecanemab therapy. The AURs recommends a screening MRI and periodic along with symptom‐triggered MRI surveillance to detect asymptomatic and symptomatic ARIA and address it appropriately.ConclusionClinician and institutional preparedness are mandatory for the use of lecanemab. This includes training of neurologists, geriatric psychiatrists, radiologists, primary care, emergency room and intensive care physicians, and stroke neurologists in safety monitoring and treatment of symptomatic ARIA.
Cognitive Aspects of Prymary Sjögren’s Syndrome
Authors: Macedo Lorena Barbosa , Foss Maria Paula 
Published: December 2023

AbstractBackgroundSjögren’s primary syndrome (PSS) is an autoimmune disease that affects the tear line exocrine glands and saliva and may also interfere with the central (CNS) and peripheral nervous systems. PSS patients presenting with the disease can be divided into a profile characterized by the greater intensity of symptoms such as pain, fatigue, and dryness and another with fewer symptoms but a more severe prognosis. Therefore, it was verified the involvement of the CNS through neuropsychological evaluation in the different profiles of PSS.Method24 women, 11 with profile 1 (more intense symptoms, PSS1), and 13 with profile 2 (worse prognosis, PSS2), performed neuropsychological assessment composed by: MoCa, Boston reduced version, FAS. Mann Withney’s nonparametric test compared the groups, and the variables were correlated by Spearman coefficient of SPSS 23.ResultThere was a predominance of women (100%) with a mean age of 49.91 ±10.56 years and schooling of 7,83 ± 2.79 years. The comparison between PSS1 and PSS2 showed no significant difference between age (PSS1 = 52,72±8.83; Pss2 = 47.53±11.64; p = 0.257), schooling (PSS1 = 528.18± 2.67;; Pss2 = 7.53±2.96, p = 0.451) and between the tests for profiles, Moca (p = .636), Boston (p = .194), FAS (p = 1.00). Between the tests, we can verify significant positive correlations between Moca x Boston; Moca x FAS_F; Moca x FAS_A; Moca x FAS_S; Moca x FAS, and the FAS variables among themselves. The correlation between age and schooling was not significant.ConclusionThere was no difference between age and schooling or neuropsychological assessment, considering the techniques used. Then, cognition may be preserved in this sample, reflecting a non‐involvement of the CNS in this disease. However, future studies that are being conducted need to complement these results by expanding the sample or using other instruments.
Validation of A Novel MAO‐B PET tracer [18F]SMBT‐1 on postmortem human brain samples
Authors: Harada Ryuichi , Yiqing Du , Yokoyama Yuka , Ishiki Aiko , Kudo Yukitsuka , Tashiro Manabu , Furumoto Shozo , Okamura Nobuyuki 
Published: December 2023

AbstractBackgroundNeuroinflammation in various neurodegenerative conditions involves reactive astrogliosis that overexpresses glial fibrillar acid protein (GFAP) as well as monoamine oxidase‐B (MAO‐B). Recently, we developed a reversible MAO‐B PET tracer, [18F]SMBT‐1. Initial clinical PET studies demonstrated that [18F]SMBT‐1 showed higher regional binding not only amyloid (Aβ)‐positive Alzheimer’s disease (AD) but also Aβ‐negative elderly cognitively normal (CN). To validate initial clinical finding, we investigate the binding of [18F]SMBT‐1 in postmortem human brain samples.Methods
In vitro autoradiography of [18F]SMBT‐1 (MAO‐B), [18F]Florbetaben (Aβ), and [3H]MK‐6240 (Tau) was performed using postmortem brain sections from CN and AD. In vitro binding assay of [18F]SMBT‐1 was performed against brain homogenates from CN, argyrophilic grain disease (AGD), Lewy body disease (LBD), and frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP). GFAP levels were measured to investigate the association with tracer binding. Double immunohistochemistry of MAO‐B and A1/A2 reactive astrocyte markers were performed to understand the relationship of astrocytic phenotype in MAO‐B expressing astrocytes.ResultsHigher specific binding of [18F]SMBT‐1 was observed in Aβ‐positive/Tau‐positive AD brain sections. Interestingly, intense patchy signal of [18F]SMBT‐1 was observed in Aβ‐positive/Tau‐negative CN brain section, which was partially co‐localized with that of Aβ detected by [18F]Florbetaben. These observations were consistent with the findings of clinical [18F]SMBT‐1 PET study. In the brain samples of AGD, LBD and FTLD‐TDP, the amount of [18F]SMBT‐1 binding was correlated with GFAP levels. Double immunostaining demonstrated that MAO‐B was expressed in both A1 and A2 reactive astrocytes.ConclusionsSignificant [18F]SMBT‐1 binding was detected in the postmortem brains of both AD and Aβ‐positive/Tau‐negative CN, reflecting reactive astrogliosis induced by early Aβ accumulation. [18F]SMBT‐1 would be a promising marker for reactive astrogliosis in neurodegenerative diseases.
Dynamic imaging and targeted degradation of the RNA‐binding protein hnRNP A2B1 using nanobodies
Authors: Cho Yongku P , Pirhanov Azady 
Published: December 2023

AbstractBackgroundRNA‐binding proteins (RBP) are a primary component of stress granules, a key indicator of various cell stress responses. Recently, the heterogeneous nuclear ribonucleoprotein hnRNP A2B1 emerged as a primary protein that preferentially interacts with tau oligomers than tau monomers. Here we studied the dynamics of hnRNP A2B1 in cultured cells and primary neurons using a novel nanobody reagent that enables live‐cell imaging.MethodWe screened a recombinant nanobody library to identify nanobodies (Nbs) that bind to hnRNP A2B1. The Nbs were designed to bind to all isoforms of hnRNP A2B1. We applied protein engineering approaches to improve the binding affinity of the identified Nbs. Live cell imaging was conducted in cultured cell lines and primary mouse hippocampal neurons. We also generated Nb‐E3 ligase fusions for targeted degradation of hnRNP A2B1.ResultThe Nbs revealed an unexpected localization of hnRNP A2B1 previously not observed using GFP fusions. We observed bright puncta throughout the cytoplasm in addition to typical nucleoplasmic distribution of hnRNP A2B1. The hnRNP A2B1 puncta were co‐localized with exosomal markers. In cell lines, the nucleoplasmic hnRNP A2B1 was dramatically reduced during mitosis, while the cytoplasmic puncta did not change, suggesting cell cycle‐dependent nucleocytoplasmic translocation. The Nb‐E3 ligase fusion constructs caused a significant reduction in hnRNP A2B1, lowering the level by 60%.ConclusionThese novel tools will greatly aid the study of endogenous hnRNP A2B1 dynamics and function. Isoform‐dependent localization of hnRNP A2B1 and whether it is involved in protein loading to exosomes remains to be studied.
The NC Registry for Brain Health: Increasing Access to Brain Health Information and Research in Underserved & Under‐represented Communities
Authors: Chanti‐Ketterl Marianne , Dewees Rachel A , Bozoki Andrea , Price Stephen Russ , Martin Patrick McPhail , Edmonds Henry , Adams Latorius S , Williams Kelvin , Gaven Julie , Matchar Bobbi , Herron Susan , Ries Michelle G , Plassman Brenda L , Byrd Goldie S. , Welsh‐Bohmer Kathleen A. ,   the NC Registry for Brain Health
Published: December 2023

AbstractBackgroundDiverse racial/ethnic representation in scientific studies is crucial for generalizability of results and development of potentially effective treatments. Racially diverse registries with research ready individuals have the potential to fill this gap. However, despite having signed up as part of a research registry and being invited to participate in clinical trials, many do not participate. To better understand research participation, the NC Registry for Brain Health surveyed its members to identify the characteristics of those likely to participate in research studies, their views on research, expectations when joining the group, and impediments to participation.MethodThe NC Registry for Brain Health has been state‐funded since 2018 with goals of increasing access for all to information and research opportunities in brain health. Focused recruitment to under‐served and under‐represented groups across the State occurs through community outreach events sponsored by a five member university network. An email survey was sent to the 5,946 Registry members enrolled as of October 15, 2021.ResultApproximately 10% (n = 576) responded to this anonymized survey. Most were older women with high levels of formal education (Table 1). Despite the Registry’s demographics of 28% African American enrollees, only 8% of the survey respondents self‐identified as African Americans. Most individuals joined the Registry for the joint purpose of getting involved in research and receiving information about brain health (75%). When asked to describe what “brain health research” means, most reported studies involving dementia risk factors and memory testing. All participants had been approached to get involved in studies, but only 60% recalled getting an email invitation. The biggest impediment noted for participating in studies was inconvenient appointment times. The participants also wanted more available studies and more information about the opportunities.ConclusionThis study suggests that most participants in the Registry are seeking to be informed about brain health and have access to research opportunities at times convenient with their schedules. There was an observed gap between African Americans enrolled in the research registry and those who participated in the survey. Addressing gaps in research involvement of under‐represented groups in research is necessary to achieve inclusive representative science.
Convergent and clinical validity of a remote smartphone‐based self‐assessment of cognition, function, and behavior in early Alzheimer’s disease
Authors: Perumal Thanneer M , Wolfer Arnaud M , Veloso Miguel , Kurniawan Irma T , Aponte Eduardo A , Keita Goullou , Hagenbuch Niels , Shi Beijue , Orfaniotou Foteini , Colell Macarena Garcia Valdecases , Chatham Christopher H , Rey‐Riek Simone , Sink Kaycee M. , Watson David , Boada Mercè , Taylor Kirsten I 
Published: December 2023

AbstractBackgroundTrials in early Alzheimer’s disease (eAD) require the quantification of cognitive and functional progression. Compared with traditional in‐clinic assessments, remote assessments via digital health technologies (DHT) enable the collection of a broader palette of cognitive and functional measures at higher frequency and in patients' home environments. However, these must demonstrate validity against standard clinical outcome measures and relevant biomarkers. To this end, the present study aims to determine the reliability, convergent clinical, and functional neuroanatomic validity of a novel DHT, the Alzheimer’s Disease Digital Assessment Suite (AD‐DAS), for individuals on the AD continuum.MethodsIn total, 123 participants from 2 countries across 5 sites (3 USA, 2 Spain) participated (https://www.isrctn.com/ISRCTN17035495): 32 healthy controls (HC), 31 amyloid‐PET negative and 30 amyloid‐PET positive subjective cognitive decline (SCDn, SCDP, respectively), and 30 eAD. All participants completed standard in‐clinic neuropsychological assessments and remotely performed the AD‐DAS tasks daily for 28 days without supervision. AD‐DAS comprised 9 active tasks of cognitive/motor functioning and 4 survey questionnaires. Convergent and clinical validity analysis were performed using linear and proportional odds logistic regression modeling with age, sex, education, and site as covariates, respectively. Functional neuroanatomic validity was tested with voxel‐based morphometry (VBM) analyses with anatomic MRIs.ResultsOutcome metrics from all AD‐DAS cognitive/motor tasks correlated with their corresponding clinical comparators (ρpartial (range) = 0.16 ‐ 0.52), supporting their convergent validity. Similarly, outcome metrics from all tasks significantly differentiated the eAD from all the other groups in the expected directions (odds ratio (range) = 0.01 ‐ 61), supporting their clinical validity. The reliability of the outcome metrics ranged from good to excellent (interclass correlation coefficient (range) = 0.71 ‐ 0.91). VBM analyses provided independent and largely confirmatory results, further validating the AD‐DAS.ConclusionsThe AD‐DAS remote, smartphone‐based assessments of cognition show good to excellent test‐retest reliability, and preliminary analyses indicate that they may show convergent, clinical and exploratory functional neuroanatomic validity. Thus, these results provide a foundation for building towards the overarching goals of remote screening, prediction of progression, and monitoring of cognitive decline for future clinical trials and clinical care for preclinical and eAD.