bluuebunny/crossref_metadata_2025_split huggingface dataset:
Top‐line data from a phase 1b biomarker‐directed, proof of biology study in Alzheimer's patients treated with XPRO1595, a second‐generation treatment for immune dysfunction
Authors: Tesi Raymond , Barnum Christopher , Tansey Malu Gamez 
Published: December 2020

AbstractBackgroundTumor Necrosis Factor (TNF) is the master regulator of chronic inflammation and immune dysfunction, which play a critical role in Alzheimer's Disease (AD). The current TNF inhibitors are contraindicated for neurologic disease due to complications (i.e., cause demyelination). XPro1595 is a second‐generation inhibitor designed to overcome the limitations of the current generation of TNF inhibitors to treat neurologic disease. We have received the Part the Cloud to RESCUE Award from the Alzheimer’s Association to conduct a biomarker directed, proof of biology, Phase 1b study.Method18 patients with a diagnosis of Alzheimer’s disease and biomarkers of inflammation in the blood were eligible to participated in a 12‐week, dose escalation study to establish safety and proof of concept that XPro1595 can reduce inflammation within the CNS.ResultThis presentation will focus on the challenges and lessons of using inflammatory biomarkers for patient enrollment in AD studies along with the safety data and available efficacy data.ConclusionClinical data will be presented.
Subjective cognitive decline predicts progression to dementia in a multiracial community sample
Authors: Chapman Silvia , Rentería Miguel Arce , Avila Justina F. , Joyce Jillian L. , Manly Jennifer J. , Brickman Adam M. , Cosentino Stephanie 
Published: December 2020

AbstractBackgroundSubjective Cognitive Decline (SCD) is the perception of cognitive decline before such decline is evident on standard neuropsychological testing. SCD is believed to precede the Mild Cognitive Impairment stage of Alzheimer’s disease (AD) when objective cognitive deficits first become evident and has potential as an early marker of AD. However, studies examining SCD have largely focused on non‐Hispanic White populations, limiting its applicability to Blacks and Hispanics, who are known to be at increased risk of developing AD. This study examines the predictive utility of SCD for conversion to dementia in a racially and ethnically diverse sample.MethodParticipants were a total of 5,379 older adults enrolled in a longitudinal, population‐based study of aging. Participants were non‐demented at baseline and were 26% non‐Hispanic White, 31% Black and 44% Hispanic (67% female; age=75±6yrs). SCD was assessed with a questionnaire assessing complaints of memory difficulties. Follow ups of approximately 18‐month intervals assessed for dementia at each visit based on comprehensive assessment of everyday function and cognition. Multi‐group Cox regression models tested main effects of baseline SCD on progression to dementia, and jointly modeled death during follow up as a function of race/ethnicity. Models were adjusted for age, depressive symptoms, sex, years of education, medical comorbidity burden, and enrollment cohort.ResultSCD significantly predicted conversion to dementia in all groups (Non‐Hispanic White HR=1.65 [1.04, 2.61]; Blacks HR=1.62 [1.17, 2.24] and Hispanics (HR=1.74 [1.40, 2.17]). Although multi‐group modeling revealed no significant interactions between SCD and race (p> .05), when depressive symptoms were entered as a covariate in each model SCD significantly predicted conversion to dementia in Blacks (HR=1.77 [1.10, 2.84]) and Hispanics (HR=1.84 [1.36, 2.48]) only.ConclusionSCD predicted conversion to dementia across all racial/ethnic groups. However, when adjusting for depressive symptoms, the predictive utility of SCD remained only among Blacks and Hispanics. This pattern of findings highlights the utility of SCD as a marker of future conversion to dementia in diverse groups, while underscoring the complex association between SCD and depression. Future work should tease apart the basis of the unique pathways between depression and SCD as a function of race/ethnicity.
Mapping Alzheimer disease–associated regions in the African American population
Authors: Whitehead Patrice L. , Rajabli Farid , Hamilton‐Nelson Kara L. , Kunkle Brian W. , Reitz Christiane , Naj Adam C. , Bush William S. , Farrer Lindsay A. , Schellenberg Gerard D. , Mayeux Richard , Martin Eden R. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Pericak‐Vance Margaret A. ,   Alzheimer’s Disease Genetics Consortium (ADGC) and Collaboration on Alzheimer’s Disease Research (CADRE)
Published: December 2020

AbstractBackgroundGenetic studies in Alzheimer disease (AD) are underrepresented in African‐descent populations. The African American (AA),population, with the admixed genetic ancestry (African and European) and high African ancestral background (∼80%), provides a unique opportunity to discover African ancestry‐specific genetic factors in AD. Admixture mapping (AM) is a powerful approach for genetic mapping of complex disease in admixed populations. AM uses local ancestry estimates to identify the genetic regions of specific ancestral origins (African, and European) that are associated with AD. These regions are likely to contain risk or protective genes for AD, and identifying these regions will inform sequence analysis in these and additional datasets.MethodsAnalyses included 9050 individuals from 16 ADSP and ADGC cohorts We estimated and inferred global ancestry using the GENESIS software that provides robust inference of genetic ancestry in the presence of known and/or cryptic relatedness. To infer local ancestry the target AA dataset was combined with appropriate reference population samples from HGDP reference panel. Local ancestry was estimated using SHAPEIT followed by RFMix. We performed AM using the GENESIS software separately on 16 different cohorts. To meta‐analyse the admixture mapping results we developed in‐house scripts to align the ancestral blocks across cohorts. We used the METAL software for meta‐analysis and STEAM software to estimate the significance threshold.ResultsWe estimated significant threshold for admixture mapping analysis in AA dataset as 7.3e‐5 using analytic approximation approach from the STEAM package. The most significant region from the meta‐analysis was found on chromosome 4p16.3 (p‐value = 1.4e‐4) failed to reach genome‐wide significance. However, n two individual cohorts ADC8 (sample size = 850) and ADGC‐CHOP (sample size = 2,869) two regions showed genome‐wide significant association with disease on chromosome 18q21.33 (p‐value = 1.2e‐6) and chromosome 19p13.3 (p‐value<2.1e‐5), respectively.ConclusionOur results confirm association of AD with the known ABCA7 genetic region on chromosome 19p13.3 through AM and suggest a genetic region for AD in AA population on 18q21.33; however, findings were not consistent across cohorts. We are in the process of analyzing data from additional AA cohorts to increase the power and allow us to dissect heterogeneity of AD in AA population.
Distinct contributions of longitudinal tau and amyloid to decline in various cognitive domains in preclinical AD
Authors: Farrell Michelle E. , Papp Kathryn V. , Jacobs Heidi I.L. , Buckley Rachel F. , Properzi Michael J. , Schultz Aaron P. , Hanseeuw Bernard , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. 
Published: December 2020

AbstractBackgroundWe sought to assess the preclinical contributions of longitudinal Aβ and tau accumulation at different baseline Aβ levels to decline across multiple cognitive domains.Method124 clinically normal older adults from the Harvard Aging Brain Study with longitudinal Aβ (PIB), tau (FTP) and cognition (PACC) were included (median follow‐up=8.0±1.0 years). The following linear mixed models examined neocortical PIB and inferior temporal (IT) FTP change effects on PACC and its component tasks and included age, sex, APOE and education as covariates: 1) Time*PIB level t0*PIB change t0‐3 on cognition t0‐8, with post‐hoc regional analyses. 2) Time*PIB level t3*FTP change t3‐8 on cognition t3‐8, because FTP was introduced at t3. Mediation analyses assessed whether the effect of PIB change t0‐3 on subsequent cognitive decline t3‐8 was mediated by IT‐FTP at t3.
ResultIncreasing PIB change‐t0‐3 was associated with declining cognition‐t0‐8 across all tasks at higher PIB‐t0 levels (Figure 1). The Digit Symbol Substitution Test (DSST) also declined with increasing PIB change at low PIB‐t0 levels (β=‐1.99, p=.002). FTP change‐t3‐5 was associated with declines at high PIB‐t3 levels for all PACC components except DSST (Figure 2). Only free recall (Free and Cued Selective Reminding Test; FCsrt‐FR) exhibited FTP change‐related decline in low PIB adults (β=‐1.70, p=.02). Mediation analyses demonstrated that FTP‐t3 mediated the effect of PIB change t0‐3 on cognitive decline t3‐8 for all PACC components except DSST, which remained associated only with PIB change (Figure 3). Regional analyses revealed different patterns of increasing PIB change associated with FCsrt‐FR and DSST decline (Figure 4).ConclusionTwo different patterns of cognitive decline were observed: 1) A tau‐mediated pattern of steeper decline across multiple domains in individuals with high Aβ. Free recall declined starting at low Aβ levels, in association with tau and accumulating Aβ in regions important for memory retrieval. 2) A decline on the DSST associated with accumulating Aβ, but not IT tau, even in those with low Aβ. DSST involves processing speed and executive function. The broader pattern of Aβ accumulation was associated with DSST decline suggests it may reflect a general cognitive slowing in response to Aβ‐mediated changes in synaptic transmission.
Sex differences in cortical microstructural changes in asymptomatic individuals at risk for Alzheimer’s disease
Authors: Chance Steven A , Torso Mario , Chiesa Patrizia Andrea , Lemercier Pablo , Vergallo Andrea , Lista Simone , Potier Marie‐Claude , Dubois Bruno , Hampel Harald ,   the INSIGHT‐preAD Study group
Published: December 2020

AbstractBackgroundThe preclinical phase of Alzheimer’s disease (AD) is characterized by cortical microstructural changes before the appearance of clinical symptoms. Previous studies have shown that women can present significantly faster age‐related decline than men [Filon et al., 2016; Barnes et al., 2005; Ferretti et al., 2018]. The aim of the present study was to investigate the impact of sex in whole brain cortical changes in an asymptomatic population at risk for AD.MethodA total of 167 subjects (68 males and 99 females) recruited in the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study, were included in the present work. The T1 structural and diffusion tensor imaging (DTI) scans acquired at baseline and after 24 months, were analysed to calculate 3 novel cortical diffusion measures (AngleR, PerpPD and ParlPD) [McKavanagh et al., 2019] and the mean diffusivity (MD). An independent sample t‐test was used to assess group differences in demographic, clinical and MRI volumetric values. A linear regression analysis was performed to investigate the role of sex, age and APOE genotype on baseline cortical values. The repeated measures ANOVA was used to assess cortical diffusion differences at baseline and follow‐up.ResultMen compared with women showed higher angle between the principal diffusion direction and the radial minicolumn direction across the cortex at the baseline (p=0.001). No demographic, clinical nor brain volumetric differences between men and women were detected. The linear regression analysis revealed that only sex explains differences in AngleR values (p=0.001). The repeated measures ANOVA showed a significant effect of time (p=<0.001) and a significant interaction between time and sex (p=0.013), with a higher progression rate in women compare to men.ConclusionThese findings indicate that sex has a significant effect on cortical changes and in their progression rate. The DTI measures could have a central role in enabling individual’s specific characterization and may be informative for the development and assessment of potential drug targets that are specific for each subgroup.
Creating technology for and with people with MCI and dementia in the workplace
Authors: Shastri Karan , Dove Erica , Marashi Sheida , Boger Jennifer , Astell Arlene J 
Published: December 2020

AbstractBackgroundThe potential of technology to assist people who are diagnosed with MCI or early dementia (EOD) whilst still working is under‐explored.MethodSemi‐structured interviews and participatory design sessions were held with people working with MCI/EOD and family care partners aged between 45‐65 years to identify their technology preferences, challenges they faced, redesigning their workspace and future solutions. Sessions were video and audio recorded for analysis of the problems with NVivo 12 and to elicit design considerations.ResultsFive themes emerged from the interviews and participatory sessions: 1. Challenges at work, 2. Accommodations at work, 3. Diversity of supportive technologies, 4. Pressure points and strategies, and 5. Potential ideas and design cues.ConclusionPeople working with MCI/EOD currently appropriate technology to support them, have clear ideas of the challenges they face and design suggestions for future technological supports. These should be viewed within the ecosystem surrounding individuals working with MCI/EOD, particularly workplace legislation and stimulus for employers to meet their needs.
Agora: An open platform for exploration of Alzheimer’s disease evidence
Authors: Greenwood Anna K. , Gockley Jake , Daily Kenneth , Aluthgamage Duminda , Leanza Zoë , Sieberts Solveig K. , Woo Kara H. , Simon Stockard , Gendel Alina , Thyer Tess , Do Khai , Doerr Megan , Peters Mette A. , Omberg Larsson , Logsdon Benjamin A. , Mangravite Lara M. 
Published: December 2020

AbstractBackgroundNew therapies for treating Alzheimer’s Disease (AD) are urgently needed. Discovery‐based research approaches have identified a host of promising new AD targets across a spectrum of therapeutic hypotheses. However, progress to validate selected targets and develop new experimental reagents and therapeutics requires efforts beyond the focus of any single research group. We have built the Agora site as an open repository that publicly shares information about new AD targets to facilitate target evaluation by the broader AD research community.MethodAgora aggregates information and experimental resources in support of nascent AD targets. We are expanding Agora to catalog evidence and experimental reagents being generated by the Open Drug Discovery Center for AD (Open‐AD).ResultAgora is available at https://agora.ampadportal.org. Agora presents a list of nominated targets stemming from the Accelerating Medicines Partnership in AD (AMP‐AD) consortium and the broader AD research community. Agora also hosts interactive visualizations designed to support non‐bioinformaticians in the evaluation of data from RNAseq, proteomic, and metabolomic studies. Updates to Agora in support of the new Open‐AD center include 1) presentation of individual scorecards for nominated targets based on multiple lines of evidence and 2) a new exploration framework in which targets are mapped onto therapeutic hypotheses.ConclusionAgora is a platform to enable the AD research community to unite around promising target hypotheses.
Illiteracy and risk of mild cognitive impairment among Mexican older adults: Data from the Mexican Health and Aging Study (MHAS)
Authors: Rentería Miguel Arce , Vonk Jet M.J. , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Barral Sandra , Tosto Giuseppe , Manly Jennifer J 
Published: December 2020

AbstractBackgroundMild cognitive impairment (MCI) is a diagnostic entity associated with increased risk of incident dementia. Prior epidemiological studies have associated illiteracy and low to no formal education with increased prevalence of MCI and dementia. A recent study using a robust neuropsychological approach with the harmonized cognitive assessment ancillary study (Mex‐Cog) of the Mexican Health and Aging Study (MHAS) found that low education as well as older age, depression, diabetes, and rurality were independently associated with MCI among older adults. Rates of illiteracy are relatively high among older adults in Mexico, due to limited access to formal education, but some people attained literacy despite not attending school. To assess the unique contribution of literacy to MCI independent of educational achievement in a Mexican population, we evaluated literate and illiterate older adults with no formal schooling.MethodAnalyses included a sample of literate and illiterate non‐demented adults over the age of 55 living in both urban and rural areas of Mexico who reported that they never attended school (N = 231). MCI diagnosis was assigned based on a comprehensive cognitive assessment for domains of memory, executive functioning, language, and visuospatial ability. Cognitive impairment was defined using a robust norms approach and a 1.5‐SD cut‐off per cognitive domain correcting for age, years of education, and sex. Multinomial logistic regressions evaluated the association of self‐reported literacy, age, and sex with risk of MCI. We then evaluated whether the relationship between literacy and MCI remained after controlling for sociodemographic and health factors.ResultIlliteracy was associated with increased risk of MCI (OR=6.05 [3.33, 11.34]) compared to literate participants. The relationship between literacy and risk of MCI persisted after taking into account depression, rurality, hypertension, and diabetes.ConclusionWe found that illiteracy was independently associated with higher risk of prevalent MCI. Our findings suggest that independent of formal education, attainment of literacy has a long‐lasting impact on brain health at older ages. Future studies in low socioeconomic populations should consider functional literacy as a powerful predictor of cognitive function in old age.
Longitudinal online weekly health reports of non‐cognitive symptoms and events can differentiate incident MCI from stable cognitively healthy older adults
Authors: Kaye Jeffrey , Mattek Nora , Beattie Zachary , Sharma Nicole , Riley Thomas , Dodge Hiroko H. 
Published: December 2020

AbstractBackgroundChanges in mood, loneliness, pain, and need for assistance may be potential early markers of cognitive decline in older adults. These changes can be subtle, and fluctuating, and thus easily missed during intermittent clinic visits. Continuous long‐term monitoring of these self‐reported internal states and needs, and their relationship to developing cognitive impairment has not been assessed.MethodWeekly online reports of health‐related activities and mood in relation to MCI were assessed over four years in volunteers participating in the Oregon Life Laboratory, a study using home‐based unobtrusive remote sensing and monitoring of physical, cognitive, behavioral, physiological, and health‐related activities. Participants were older adult computer users living in retirement communities and free‐standing homes.ResultThe analytic sample included 129 cognitively healthy volunteers with a mean monitoring period of 2.9 ± 1.2 years completing 16,738 online surveys. Mean age was 83.5 ±7.8 years, mean education was 15.7 ± 2.7 years, and 76% were female. Twenty‐two participants (17%) developed MCI or dementia while 107 remained cognitively healthy. Results from longitudinal models with dichotomous outcomes including 1) loneliness, 2) low mood, 3) pain intensity and pain interference, and 4) in‐home assistance were run adjusting for covariates. Over time, those destined to develop MCI reported: 1) more loneliness (p=0.049), 2) more low mood (p=0.07), 3) greater pain intensity (p=0.026) and pain interference (p=0.011), and 4) needing more in‐home assistance (p=0.022) than those remaining cognitively healthy. Baseline standard clinical scale scores assessing these symptoms were not clinically concerning nor predictive of MCI. Baseline mean pain intensity scores (range: 0‐9) were 2.2 ± 2.0 among incident MCI and 1.8 ± 2.0 in stable cognitively healthy participants (p=0.23). Geriatric Depression Scale baseline scores were 1.0 ± 1.5 in incident MCI and 1.1 ± 1.7 in stable cognitively healthy participants (p=0.82).ConclusionContinuous home‐based online assessment of non‐cognitive aspects of function or internal states (loneliness, mood, pain, needing more assistance) can be sensitive early indicators of changes in brain function leading to cognitive decline. These clinically important measures may reflect both direct as well as indirect relationships to underlying neuropathology.
Single nucleus and bulk homogenate RNA‐sequencing comparison of vascular endothelial growth factor family associations with Alzheimer's disease
Authors: Moore Annah M. , Mahoney Emily R. , Dumitrescu Logan , De Jager Philip L. , Koran Mary Ellen I. , Petyuk Vladislav A. , Robinson Renã A.S. , Ruderfer Douglas M. , Cox Nancy J. , Schneider Julie A. , Bennett David A. , Jefferson Angela L. , Hohman Timothy J. 
Published: December 2020

AbstractBackgroundPrevious work from our group and others has suggested that the VEGF family of genes and proteins may be involved in the pathophysiology of Alzheimer’s disease (AD) and associated cognitive decline. Using dorsolateral prefrontal cortex (DLPFC) RNA sequencing (RNA‐seq) data (N = 531), we have characterized robust associations between gene expression of four family members (VEGFB, PGF, FLT1 and FLT4) and AD diagnosis, neuropathology, and associated cognitive decline. More specifically, increased brain expression of these genes was associated with worse outcomes. Single nucleus RNA sequencing (snRNA‐seq) of DLPFC became available for a small subset of this cohort (N = 48). We set out to assess associations between gene expression of these family members and cognitive decline using snRNA‐seq and compare to homogenate RNA‐seq findings to better understand the cell specificity of observed effects.MethodLongitudinal cognitive and snRNA‐seq data from astrocytes, endothelial cells, microglia, oligodendrocytes, oligodendrocyte progenitor cells, pericytes, excitatory and inhibitory neurons were obtained from the Religious Orders Study and Rush Memory and Aging Project cohort studies. Linear regression and mixed‐effects regression were used to assess VEGF gene expression associations with global cognition and cognitive change, respectively. Models covaried for age at death, sex and postmortem interval and were subjected to the Benjamini‐Hochberg procedure to correct for multiple comparisons within cell types.ResultPGF and FLT4 expression across cell types was too low to be considered in statistical models. FLT1 expression was largely restricted to endothelial cells. while VEGFB expression was highest in neurons and astrocytes. Interestingly, inhibitory neuron VEGFB expression approached a positive association with cross‐sectional cognition (p.fdr = 0.055), in opposition to the direction of our bulk homogenate finding. In contrast, oligodendrocyte VEGFB was negatively associated with cross‐sectional (p.fdr = 0.039) and longitudinal (p.fdr = 0.053) cognition, consistent with our previous findings in bulk.ConclusionSingle nucleus VEGF expression analyses suggest that homogenate VEGFB associations with AD outcomes are driven by oligodendrocytes. VEGFB is a neuroprotective factor, and the observed upregulation in VEGFB could represent a stress response to AD pathology. The highly restricted expression of FLT1 to endothelial cells suggests that the relationship between FLT1 and cognitive trajectory reflects alterations in endothelial signaling.