bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inducible microRNA‐34a overexpression impairs cognition and promotes Alzheimer's pathology
Authors: Freitas Raul , McDonald Katherine , Wang Hanyun , Sarkar Saumyendra , Corbin Deborah , Bix Gregory J , Simpkins James W , Engler‐Chiurazzi Elizabeth 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD), a chronic neurodegenerative condition resulting from pathological brain aging, is the most common cause of geriatric dementia and is likely polygenic in origin. The discovery of microRNAs (miR), small, endogenous, non‐coding, and highly conserved RNAs that regulate post‐transcriptional expression of potentially hundreds of genes, has revealed new drivers and therapeutic targets of AD pathogenesis. Research from our group and others indicates that miR‐34a may be a promising candidate.MethodWe aimed to interrogate the dementia‐associated cognitive and neurobiological consequences of miR‐34a stimulation in vivo. We generated a global doxycycline (Doxy)‐inducible miR‐34a expression mouse model (miR34a+/‐ 2X (TetR‐TetO‐miR34a). Three‐month‐old male and female miR‐34a+/‐ mice were treated for ∼90 days with either normal drinking water or Doxy (2mg/ml) to induce miR‐34a expression (N= 7‐8 mice/group) and evaluated for cognitive and neurobiological factors disrupted in other transgenic AD mice. To ascertain brain‐ and cell type‐specific vulnerabilities of miR‐34a overexpression, we also generated a mutant mouse line in which miR‐34a overexpression is restricted to excitatory neurons using a CaMKIIα driver.ResultDoxy‐treated miR‐34a+/‐ mice showed T/Y‐maze memory deficits, coinciding with upregulated miR‐34a expression in all brain regions assayed. They also showed evidence of known AD neuropathologies, including reduced NMDA2B glutamatergic receptor expression, altered amyloid precursor processing (alpha‐secretase), and increased phosphorylated tau. Experiments to determine consequences of brain‐specific miR‐34a overexpression are ongoing.ConclusionIn conclusion, miR‐34a appears to contribute to an AD‐like phenotype. Future work will utilize this Tet‐inducible system to explore age‐related susceptibility to, and capacity for recovery from, the cognitive and neuropathological consequences of miR‐34a overexpression.
Concerted alterations of functional connectivity and WM integrity in relationship to early amyloid deposition
Authors: Lorenzini Luigi , Orso Beatrice , García David Vállez , Pontillo Giuseppe , Ingala Silvia , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Waldman Adam , Ritchie Craig W. , Gispert Juan Domingo , Visser Pieter Jelle , Mutsaerts Henri JMM , Tijms Betty M. , Wink Alle Meije , Barkhof Frederik 
Published: December 2022

AbstractBackgroundEarly amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to amyloid deposition may increase our understanding of the neuropathological processes underlying AD.MethodWe included 648 non‐demented participants from the European Prevention for Alzheimer’s Dementia (EPAD) cohort vIMI baseline data release. The cut‐off for cerebrospinal fluid (CSF) amyloid‐β positivity (A+) was defined at <1000pg/mL (Elecsys assay). Functional connectivity was estimated with functional eigenvector centrality (EC) from the resting state functional MRI. White matter (WM) integrity was estimated with fractional anisotropy (FA), computed on diffusion MRI. Both measures were computed at the voxel level within the gray and white matter, respectively. First, we used linear regression models to investigate differences between A+ and A‐ participants within each modality separately, adjusting for age, sex, and site. In the whole group, we performed sparse canonical correlation analysis (sCCA) on functional and structural measures, identifying shared components between the two modalities. Individual sCCA scores were compared between amyloid groups using a generalized linear model (GLM). To evaluate this association in A+ individuals, the same sCCA analysis was performed normalizing the structural and functional matrices using the mean and SD from A‐ participants.ResultsSample characteristics are provided in Table 1. Differences in voxelwise EC and FA between amyloid groups are shown in Figure 1. In the whole group, sCCA analysis showed that EC in the default mode, executive and cerebellar networks covary with FA in parietal, temporal and cerebellar areas (Figure 2). sCCA projections were differentially expressed according to amyloid status (Table 2). In A+ participants, stronger association of EC in the posterior DMN and cerebellum with FA in the splenium and brainstem were found (Figure 3).ConclusionUsing a data‐driven multivariate analysis, we identified concerted patterns of functional and structural changes that occur with amyloid deposition in the predementia stage. These results highlight the importance of multimodal assessment for early diagnosis.
Pharmacodynamics Assessment of Aducanumab in 5XFAD mice: A MODEL‐AD PTC Study
Authors: Territo Paul R , Quinney Sara K , Masters Andrea R , Haynes Katy A , Cope Zackery A , Little Gabriela , Williams Sean‐Paul , Meyer Jill A , Peters Jonathan , Figueiredo Lucas , Persohn Scott C , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Seyfried Nicholas T. , Onos Kristen D , Sasner Michael , Howell Gareth R , Carter Gregory W , Oblak Adrian L , Lamb Bruce T , Rizzo Stacey J Sukoff 
Published: December 2022

AbstractBackgroundThe Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice.MethodsInitial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry.ResultsPK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress.ConclusionschAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.
The Institute on Methods and Protocols for Advancement of Clinical Trials for ADRD (IMPACT‐AD): An update after two years of conduct.
Authors: Grill Joshua , Berkness Tyler , Carrillo Maria C. , Snyder Heather M. , Aisen Paul , Sperling Reisa A. , Petersen Ronald C. , Aggarwal Neelum T. , Bell Karen L. , Burns Jeffrey M. , Donohue Michael C. , Dodge Hiroko H , Espeland Mark A. , Gillen Daniel L. , Geldmacher David S. , Heidebrink Judith L , Jicha Gregory A , Olichney John M. , Rafii Michael S , Rentz Dorene M. , Salloway Stephen P. , Sethuraman Gopalan , Smith Amanda G , Raman Rema 
Published: December 2022

AbstractBackgroundWe developed the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) to address the shortage of qualified investigators with adequate training and expertise to conduct Alzheimer’s Disease (AD) and AD Related Dementias (ADRD) clinical trials.MethodWe describe the experience of the first two years of funding of the IMPACT‐AD course, specifically the rates of applications to the course, descriptive summaries of the accepted trainees, and the measures of participant satisfaction and learning.ResultOver the first two years of the course, we received 195 eligible applications to the course. Most (n = 121, 62%) applicants were female and nearly half self‐reported as being African American/Black, Asian, or Pacific Islander race and/or Hispanic/Latino ethnicity. Forty‐one applicants (21%) indicated that they were the first in their family to attend collegeOf 69 total trainees accepted to the course (36% acceptance rate), a majority (n = 44, 64%) were female. Twenty‐eight (41%) self‐reported as being African American/Black, Asian, or Pacific Islander race and eleven (16%) were of Hispanic ethnicity. Fourteen trainees (20%) identified as being the first person in their family to attend college. Among trainees, 24 (35%) were MDs, 30 (43%) were PhDs, and 9 (13%) held master’s degrees.Course lecture topics were rated, on average, as “essential” or “valuable” by 98% of trainees. Across lecture topics, on average, 48% of trainees rated their prior knowledge of topics as “very strong” or “strong,” and 11% of trainees rated their prior knowledge as “weak.” Overall, 52% of trainees evaluated their change in knowledge based on the lectures as “very much increased,” 46% as “somewhat” or “slightly” increased, and 2% as “no change.” Results were similar for the two tracks. Based on pre‐ and post‐course assessments, trainees improved their knowledge of covered content (from 62% to 79% correct responses on knowledge assessments).ConclusionThe IMPACT‐AD course is achieving its mission of educating and diversifying the next generation of ADRD trialists.We thank Dr. Laurie Ryan and Dr. Kristina McLinden from the National Institute on Aging for their key contributions in leadership and scientific guidance of IMPACT‐AD.
NIAGADS Alzheimer’s Genomics Database: version GRCh38
Authors: Greenfest‐Allen Emily , Kuksa Pavel P. , Kuzma Amanda B , Valladares Otto , Lee Wan‐Ping , Wheeler Nicholas R. , Bush William S. , Leung Yuk Yee , Stoeckert Christian J , Wang Li‐San 
Published: December 2022

AbstractBackgroundThe Alzheimer’s Genomics Database (GenomicsDB) is an interactive knowledgebase for Alzheimer's disease (AD) genetics that offers a platform for data sharing, discovery, and analysis to accelerate research on AD and AD related dementias (ADRD). The resource provides unrestricted access to GWAS summary statistics datasets, variant annotations, and meta‐analysis results deposited at the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). Here we introduce an updated version of the GenomicsDB, now mapped against the latest human genome assembly, GRCh38.MethodThe GenomicsDB allows users to interactively mine AD/ADRD summary statistics datasets or visually inspect them and compare with annotated variant tracks and GRCh38 aligned functional genomics tracks from the FILER functional genomics repository (Kuksa et al. 2022). Available tracks include key AD datasets from large‐scale sequencing projects such as IGAP (Lambert et al. 2013; Kunkle et al. 2019) and the ADGC (e.g., Naj et al. 2011) that have been lifted over from earlier genome builds. Available annotated variants include those from the AD Sequencing Project’s (ADSP) Release3 WGS, called from nearly 17k samples. All variants reported in the GenomicsDB are annotated using an assembly specific version of ADSP annotation pipeline (Butkiewicz et al. 2018). The GenomicsDB provides a REST API for programmatic access. Supported queries return complete annotations for single or bulk lookups of GenomicsDB entries (genes, variants, genomic loci) and ranged queries of datasets as JSON documents.ResultThe GenomicsDB currently hosts >70 datasets and reports >150 million annotated variants from the ADSP and 23 AD/ADRD GWAS studies, mapped to GRCh38. Keeping up with community standards allows this resource to provide ongoing support for AD/ADRD research by making it possible to integrate AD/ADRD relevant `omics datasets generated by the ADSP and others who have adopted GRCh38 as their reference genome.ConclusionThe NIAGADS Alzheimer’s Genomics Database v. GRCh38 (www.niagads.org/genomics) provides an up‐to‐date and accessible platform that facilitates unrestricted sharing of genetic knowledge underpinning AD/ADRD. To best serve our user community, NIAGADS will continue to provide the GRCh37.p19 version of the Alzheimer’s Genomics Database (including programmatic access) in archival format.
Leveraging Natural Language Processing to Identify Caregiver Availability for Patients with ADRD from Electronic Medical Records
Authors: Mahmoudi Elham , Wu Wenbo , Najarian Cyrus , Aikens James , Bynum Julie , Vydiswaran V. G. Vinod 
Published: December 2022

AbstractBackgroundPrior literature has posited that caregiver availability can potentially prevent adverse health events such as hospital readmissions in the ADRD population. Identifying caregiver availability for patients with Alzheimer’s disease and related dementia (ADRD) can inform healthcare systems and hospital administrations on appropriate discharge planning. Caregiver availability is an important and influential domain in assessing risk of hospital readmissions. However, caregiver availability data is not systematically collected in our healthcare system. Our main objective was to use medical notes (from physicians, nurses, or social workers) to assess caregiver availability and types of caregivers for hospitalized patients with ADRD.MethodWe used 2016‐2019 telephone‐encounter medical notes from a single institution. Rule‐based natural language processing (NLP) was used to develop an algorithm to identify whether the patient (1) resides at home; (2) resides at an institution; (3) has a formal caregiver; and (4) has an informal caregiver. We evaluated the data at the patient level. We used chart abstraction as the “gold standard,” and examined the validity of the algorithm for both training (n = 749) and test sets (n = 227).ResultThe result from our test set indicated a high level of accuracy and reliability for identifying an informal caregiver (F1 = 0.942; accuracy = 0.947, sensitivity = 0.970, and specificity = 0.928). Identifying whether the patient lived at an institution was the least reliable measure (F1 = 0.638, accuracy = 0.899, sensitivity = 0.512, specificity = 0.978). The most common causes of misclassifications were: (1) incomplete or misspelled names of the facilities; (2) past/uncertain/undecided situations; (3) lack of specificity; (4) use of uncommon abbreviations; and (5) irregular use of templates.ConclusionOur NLP algorithm was able to identify whether the patient lived at home vs. an institution and whether the patient had a formal or informal caregiver. There is merit in continuing the NLP approach to identify more granular, caregiver‐related information (e.g., type, hours available, etc.). More effort is needed towards generalizing the algorithm. This information can be used by other healthcare systems to detect ADRD patients who do not have a caregiver at home and may be at risk of adverse events including readmission.
Cross‐ancestry effect of APOE on cognitive performance
Authors: Harerimana Nadia V. , Li Clara , Zhu Carolyn W , Sano Mary , Grossman Hillel , Goate Alison , Andrews Shea J 
Published: December 2022

AbstractBackgroundAlzheimer's disease (AD) is more prevalent in populations of non‐European ancestry, with Black and Hispanic adults 1.5 and 2.5 times more likely to develop AD respectively. Health disparities in AD could be explained by race and ancestry, where race captures risk factors due to socio‐economic aspects of health and ancestry captures the biological mechanisms influenced by genetic variation. The APOE ε4 allele is the most significant genetic risk factor for AD; however, the risk conferred by APOE ε4 differs across populations. Here, we investigate the interactive effect of race, ancestry and APOE on episodic memory performance.MethodsEpisodic memory at last assessment was measured using the Consortium to Establish a Registry for Alzheimer’s Disease Word List Memory Task in ∼500 participants from the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai (ISMMS), including 82 African American, 118 Hispanics, 117 Asian Americans, and 275 White participants. Genetic ancestry was determined using principal component analysis; global ancestry proportions using ADMIXTURE; and local ancestry in the APOE locus using RFMix. The interactive effect of APOE and genetic ancestry, global ancestry proportions, and local ancestry locus on episodic memory performance was evaluated using linear regression models adjusting for age, sex, education, telehealth/in‐person visit, and year of visit.ResultsAdmixed American and African genetic ancestry assignments showed an interaction with APOE (African: p‐value=0.023 and Amerindian: p‐value=0.002). In addition, higher proportion of African and Admixed American global ancestry showed significant interactions with APOE (African: p‐value=0.032 and Admixed American: p‐value=0.029). Lastly, ancestry local to APOE region showed an interaction with the APOE e4 allele in Admixed Americans such that an Admixed American background was associated with better cognitive performance in comparison to a European ancestral background (p‐value=0.008).ConclusionsOur study showed that ancestry modifies the effect of APOE on cognitive performance. Future work needs to evaluate potential confounders associated with social determinants of health and ascertainment bias during enrollment, including age at assessment and visit type. In sum, this study corroborates a role of ancestry in modifying APOE associated AD risk.
Sleep, self‐reported ocular health, and cognition in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL‐Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Mahanna‐Gabrielli Elizabeth , Kuwayama Sayaka , Tarraf Wassim , DeBuc Delia Cabrera , Cai Jianwen , Daviglus Martha L , Joslin Charlotte , Lee David J , Mendoza‐Santiesteban Carlos , Stickel Ariana M , Zheng Diane , González Hector M , Ramos Alberto R 
Published: December 2022

Abstract/ProposalBackgroundVisually impaired individuals may experience increased frequency of sleep/wake disorders, fragmented sleep, insomnia, and short sleep duration. Visual impairment and sleep disorders can have downstream effects on cognitive functioning.MethodSample included n = 590 (unweighted) HCHS/SOL Miami Field Center participants ages 45‐74 at baseline who returned for cognitive examination on average 7‐years later (SOL‐INCA). Participants completed validated ocular (National Eye Institute Visual Functioning Questionnaire; NEI‐VFQ), validated sleep questionnaires for sleepiness, insomnia, sleep duration and objective measures of sleep apnea visit‐1 (2008‐2011). They also completed a battery of neurocognitive tests for verbal episodic learning and memory (Brief Spanish English Verbal Learning Test), verbal fluency (Controlled Oral Word Association), processing speed and executive function (Digit Symbol Substitution) at visit‐1 and at SOL‐INCA. Two additional measures of processing speed/executive functioning were added at SOL‐INCA(Trails‐A, ‐B). We examined global cognitive performance and change using a regression‐based reliable change index, adjusting for the time lapse between visit 1 and SOL‐INCA (all measured in z‐score units). We used regression models to test whether (1) participants with sleep disorders have an increased risk for visual impairment, (2a) ocular health is associated with worse baseline and average 7‐years cognitive function and/or cognitive decline, and (2b) sleep attenuates any of these associations.ResultSleepiness (β = 0.04; p<0.01) and insomnia (β = 0.03; p<0.001) were linked to worse ocular health, and the associations were robust to adjustment for sociodemographic characteristics, acculturation, behavioral risk measures, and health conditions. Worse ocular health was linked to lower global cognitive function at baseline (β = ‐0.14; p<0.001) and on average 7‐years later (β = ‐0.16; p<0.01). The associations were consistent across all considered cognitive domains and robust to demographic adjustments. Ocular health was also associated with a change in verbal fluency (β = ‐0.17; p<0.05), but no change was observed in other cognitive domains. Sleep disorders did not attenuate any of the reported associations.ConclusionSelf‐reported ocular health was independently associated with worse language, memory, and executive function and predicted 7‐year cognitive decline in the language domain.
Is in‐home saliva collection of cortisol and DHEA‐S effective to measure stress in dementia care dyads?: A comparison between music‐based intervention group and comparison group
Authors: Kim Hyejin , Theorell Töres , Engström Gabriella , Berglund Lars , Hallinder Helena , Emami Azita 
Published: December 2022

AbstractBackgroundDespite the fact that music provides a wide array of benefits for dementia care dyads (persons with dementia and family caregivers), the increased attention to music for stress reduction in dementia care dyads has sparked questions about whether and how to effectively measure changes in stress throughout the interventions. The purpose of this study was to explore the feasibility of collecting salivary cortisol and dehydroepiandrosterone sulfate (DHEA‐S) as stress biomarkers to assess the short‐term effects of music among dementia care dyads living at home.MethodParticipants who were recruited from the memory evaluation center collected their saliva three times a day, five days a week, over the eight weeks of in‐home online music intervention. In this non‐randomized open study, we examined concentrations of endpoints morning cortisol and DHEA‐S, evening cortisol, and the ratio of cortisol to DHEA‐S. Mean values of logarithmically transformed endpoints during the last available week were compared between the intervention and comparison groups with adjustment for baseline mean values in linear regression models or non‐parametric Willett’s residual method.ResultA total of 34 dyads (34 persons with dementia and 34 family caregivers; n = 24 dyads [intervention group], n = 10 dyads [comparison group]) were included. We did not find statistically significant differences between the intervention group and the comparison group in persons with dementia. Caregivers in the intervention group had lower concentrations of morning saliva cortisol (geometric mean: 3262 pg/ml) compared to the comparison group (geometric mean: 5271 pg/ml) (p = 0.013).ConclusionThe in‐home daily saliva collection of cortisol and DHEA‐S may be feasible to examine the short‐term effects of music on stress among dementia care dyads. The findings suggest that our in‐home music intervention may help reduce stress among family caregivers who provide care to persons with dementia. Considering the small sample with high intra‐individual variation of salivary biomarkers, a randomized controlled trial with a larger sample is needed in future research.