bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF metabolites associated with CSF NeuroToolKit biomarkers
Authors: Dong Ruocheng , Lu Qiongshi , Suridjan Ivonne , Kollmorgen Gwendlyn , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Engelman Corinne D. 
Published: December 2021

AbstractBackgroundMetabolomics technology has emerged as a tool to study small molecules influenced by age, sex, genetics, lifestyle, and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with established and developing Alzheimer’s disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease.MethodThe relative abundance of untargeted metabolites was assessed via Metabolon’s UHPLC/MS platform in 161 non‐Hispanic white, cognitively unimpaired individuals from the Wisconsin Registry for Alzheimer’s Prevention (WRAP). A metabolome‐wide association study (MWAS) was conducted between 269 known CSF metabolites and CSF biomarkers, which were measured with the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays (Roche Diagnostics International Ltd): phosphorylated tau (P‐tau), total tau (T‐tau), amyloid β (Aβ42), Aβ42/40, neurofilament light protein (NFL), neurogranin, chitinase‐3‐like protein 1 (YKL‐40), S100b, glial fibrillary acidic protein (GFAP), interleukin‐6 (IL‐6), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and α‐synuclein. Linear mixed‐effects regression analyses were performed with random intercepts for individual and family adjusting for age, gender, body mass index, and years of education. The metabolome‐wide significance was determined by a false discovery rate (FDR)‐corrected p<0.05. The significant metabolites from WRAP were subsequently tested in 154 non‐Hispanic white, cognitively unimpaired individuals from the Wisconsin Alzheimer’s Disease Research Center (ADRC). Using single nucleotide polymorphisms (SNP) associated with the top metabolites, we applied linear mixed‐effects models to perform mediation analyses.ResultThe MWAS results for each NeuroToolKit biomarker from WRAP are shown in Figure 1. Metabolites were significantly associated with all biomarkers except Ab42/40 and IL‐6. Top metabolites that were associated with multiple NeuroToolKit CSF biomarkers are shown in Table 1. Significant mediation effects of stearoyl sphingomyelin(d18:1/18:0)(SM(d18:1/18:0)) were detected for P‐tau and sTREM2 (Figure 2).ConclusionThis study provides evidence that CSF metabolites are associated with AD‐related pathology through most AD CSF biomarkers and may be influenced by upstream genetic variation. The significant results for Aβ42 and Aβ40, but nonsignificant results for Aβ42/40 indicate that the metabolites associated with Aβ42 and Aβ40 may influence production of amyloid in general versus clearance of the pathological form, Aβ42.
Association of anticholinergic medication and AD biomarkers among cognitively normal late middle‐age adults: Results from the Wisconsin Registry for Alzheimer's Prevention (WRAP)
Authors: Du Lianlian , Koscik Rebecca L , Chin Nathaniel A , Bratzke Lisa C , Cody Karly Alex , Erickson Claire M , Betthauser Tobey J , Jonaitis Erin M , Hermann Bruce P , Vasiljevic Eva , Deming Yuetiva , Mueller Kimberly D , Engelman Corinne D , Chappell Richard J , Johnson Sterling C 
Published: December 2021

AbstractBackgroundStudies of anticholinergic (AC) medications (drugs that block acetylcholine neurotransmitter action) have shown associations between the AC medications use, cognitive impairment, and increased dementia risk. Associations between AC medication and AD biomarkers among cognitively normal late middle‐aged adults are unclear. This study examined associations between AC use, cognition, physical health, and amyloid PET measures.MethodsWisconsin Registry for Alzheimer’s Prevention (WRAP) participants with >=3 cognitive composite scores, free of dementia at baseline cognition (n=1262) were included in analyses of cognitive and general health measures; PET amyloid measures were examined in a subset with Pittsburgh Compound B PET imaging (PiB; n=299). Participants were classified as either taking or not taking at least one AC medication at baseline (AC+, n=437; AC‐, n=825; Table 1). Cross‐sectional analysis of baseline associations examined AC+/AC‐ differences in AD‐related cognitive composites (e.g., memory, PACC) and health markers (e.g., depression, comorbidities). Linear mixed‐effects models (LME) examined whether AC modified age‐related cognitive trajectories in APOE ε4 carriers or non‐carriers and PiB positive or negative group. Sensitivity analyses repeated models only in the high AC+ (AC score > 1) group (n=191) relative to the AC‐ group. The statistical threshold for significance was set at P < .05.ResultsMean(sd) age for AC+ and AC‐ participants was 55.4(6.4) and 53.7(6.6). The AC+ group was significantly higher than the AC‐ group on depression scores, BMI, total medications, total comorbidities, and cardiovascular problems (Table 2). The AC groups did not differ on amyloid PET measures (Table 3). At baseline cognition, the AC+ group (n=437) showed lower executive function and PACC3 scores (Figure 1). Longitudinal analyses indicated that AC+ predicted a steeper decline slope in executive function and PACC3 with effects exacerbated in individuals with AD risk factors (Fig. 2‐3, respectively). The slopes of AC + group differed significantly after age 65.ConclusionAC medication use was associated with faster cognitive decline, particularly among APOE4 carriers and those with PET‐based evidence of amyloid plaques, suggesting AC use may exacerbate AD‐related cognitive decline in the preclinical time frame. The results have implications for AC usage in older adults with AD risk or biomarker positivity.
Technical performance and biotemporal stability evaluation of Olink proximity extension assay for blood‐based biomarker discovery
Authors: Mattingly Zoe A. , Celia Amanda M. , Kuo Yi‐kai , Trombetta Bianca A. , Ramirez Christopher , LaCasse Kathryn , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E. 
Published: December 2021

AbstractBackgroundNovel biomarkers are necessary for improving differential diagnosis of Alzheimer’s Disease (AD), disease monitoring, and treatment personalization. Core cerebrospinal fluid (CSF) AD biomarkers: amyloid‐ß (Aß), total‐tau (T‐tau), and phosphorylated‐tau (P‐tau181) are strong markers of the presence of amyloid pathology, but are not suitable for measuring disease progression or drug response in a clinical trial . In this context, blood‐based biomarkers are increasingly desirable, as plasma is less invasive than CSF, enabling short‐term repeated sampling.MethodTechnical performance of Olink Proteomic’s multiplex proximity extension assay was evaluated using plasma samples from the MADRC longitudinal cohort. Over 400 analytes were measured on five off‐the‐shelf panels. Inter‐plate and intra‐plate coefficient of variations (CVs) were calculated from 3 samples run in duplicate on each plate. ANOVA was used to assess proportion of technical versus biological sources of variance. Multi‐protein investigations require consideration of multiple testing. Power calculations were performed using baseline samples from n=34 Controls and n=20 Dementia‐AD subjects to demonstrate optimal sample size for Olink studies.ResultThe majority of analyte mean CVs fell within the acceptable range for inter and intra‐plate measurements (<15%). Higher CVs were generally related to lower analyte abundance. Most analytes were relatively stable (Biotemporal CV < 15%) in control individuals year to year. ANOVA determined that the greatest source of variation in plasma was due to biological inter‐individual variability, as opposed to technical variation for all but 73 proteins. With regards to experimental power in a 450 protein experiment, a high effect size protein such as NfL required fewer than 50 samples per group to achieve confidence in observed significant differences. In contrast, the moderate effect size MCP‐1 required just under 500 samples per group when 450 proteins are measured. This decreased to n=400 if only 100 proteins are measured, and n=170 if MCP‐1 is measured alone.ConclusionOlink technology is technically robust and reliable, with biological factors being the primary source of variation for most proteins in plasma. Particularly for medium effect size proteins, sample size is an important consideration when planning experiments using this technology.
Levels of the synaptic proteins PSD‐95, SNAP‐25, and neurogranin are selectively increased in the cerebrospinal fluid of patients with Alzheimer’s disease
Authors: Kivisäkk Pia , Carlyle Becky C. , Ramirez Christopher E. , Trombetta Bianca A. , Mendes Muriel , Brock Mary , Rubel Carrie E. , Czerkowicz Julie , Graham Danielle , Arnold Steven E. 
Published: December 2021

AbstractBackgroundSynaptic dysfunction and loss occur early in Alzheimer’s Disease (AD) dementia and are closely linked to cognitive decline. Levels of both pre‐ and post‐synaptic proteins are reduced in AD brains while recent studies have shown increased levels of synaptic proteins in the cerebrospinal fluid (CSF) already in the early stages of AD, presumably due to release from degenerating synapses. We measured CSF levels of the novel post‐synaptic marker PSD‐95 together with levels of SNAP‐25 (pre‐synaptic) and neurogranin (post‐synaptic), two emerging synaptic biomarkers, in subjects with AD, other neurodegenerative diseases (OND), and controls.MethodCSF samples from 158 patients undergoing diagnostic lumbar punctures were selected from banked samples. Clinical diagnoses were established by chart review and AD status was verified by CSF ATN biomarkers. 30 subjects had mild cognitive impairment or dementia due to AD, 69 had OND, and 59 were neurological controls (NC). In addition, 30 CSF samples were obtained from healthy subjects (HC) participating in a research study. Levels of PSD‐95 and SNAP‐25 were measured by Quanterix SIMOA assays and neurogranin by an automated Euroimmun ELISA assay.ResultAll subjects had detectable CSF levels of PSD‐95, SNAP‐25, and neurogranin. Levels of all three synaptic markers were higher in AD subjects compared to subjects with OND (p=0.04, p<0.001, and p<0.001, respectively) and both control groups, while levels of SNAP‐25 and neurogranin were lower in OND subjects compared to NC (p=0.005, and p=0.025, respectively). There were tight correlations between levels of PSD‐95, SNAP‐25, and neurogranin with the strongest correlation between SNAP‐25 and neurogranin (r=0.87; r2=0.76; p<0.0001).ConclusionOur data suggest that PSD‐95 and other emerging synaptic markers are selectively increased in the CSF of subjects with AD and that levels of both pre‐ and post‐synaptic markers are tightly correlated. Specific biomarkers for AD‐associated synaptic pathology may hold promise to discriminate AD from other neurodegenerative disorders, to correlate with cognitive decline, and to monitor responses to disease‐modifying drugs reducing synaptic degeneration.
Differential impact of educational attainment on later life cognition by race/ethnicity in the Project Talent Aging Study
Authors: Thomas Marilyn D , Calmasini Camilla , Seblova Dominika , Manly Jennifer J , Lapham Susan , Peters Kelly , Prescott Carol Arlene , Mangurian Christina , Glymour M Maria 
Published: December 2021

AbstractBackgroundIncreased education reduces risk of late life cognitive impairment. However, racial/ethnic inequities in cognitive outcomes persist at all levels of education. These findings suggest the need to evaluate whether race/ethnicity modifies the association between education and cognition overall and within specific cognitive domains.MethodData are from 2,078 participants of Project Talent Aging Study, a nationally representative study of high school students sampled in 1960 and followed up for cognitive assessments at the average age of 75 years. Three cognitive domains were selected, z‐scored, and evaluated separately and as a composite measure: verbal fluency, memory/recall, and attention. We used multivariable linear regression to estimate main associations between years of education and cognitive outcomes, and then evaluated statistical interaction with race/ethnicity. All models were adjusted for age, childhood socioeconomic status, childhood self‐reported health status, number of school absences, and adolescent cognitive ability.ResultThe sample included White (81.4%), Black (9.2%), and Other race/ethnicities (9.4%). Each additional year of education was associated with higher scores on the cognitive composite measure (β=0.053; 95% confidence interval [CI]=0.031, 0.076). In the cognitive composite model with interactions, the estimate for White respondents was β=0.048 (95% CI=0.024, 0.071) and the interaction with education for Black respondents was β=0.019 (CI=‐0.062, 0.099). Within cognitive domains, each additional year of education was associated with better verbal fluency (β=0.058; 95% CI=0.035, 0.081) and attention (β=0.040; 95% CI=0.017, 0.063), but not recall (β=0.014; 95% CI=‐0.011, 0.038). Among cognitive domain‐specific models with interactions, the attention domain estimate was significantly different for Black compared to White respondents: the estimate for White adults was β=0.030 (CI=0.005, 0.055) and the interaction with education for Black adults was β=0.106 (CI=0.022, 0.189).ConclusionGreater educational attainment predicted better overall cognition, verbal fluency, and attention for US adults. Associations for verbal fluency and memory were similar for racial groups; however, education offered an additional benefit for Black adults in the attention domain compared to White adults later in life. Future research should explore whether educational opportunities and quality may have differential cognitive implications across racial/ethnic groups.
Relationship of insulin resistance and glucose to tau PET positivity
Authors: Ennis Gilda E , Betthauser Tobey J , Koscik Rebecca L , Engelman Corinne D , Anderson Rozalyn , Christian Bradley T , Asthana Sanjay , Johnson Sterling C , Bendlin Barbara B 
Published: December 2021

AbstractBackgroundInsulin resistance (IR) and hyperglycemia have been linked to increased dementia risk. In some animal studies IR and hyperglycemia have been associated with tau hyperphosphorylation. In a sample of predominantly healthy middle‐aged and older adults, we examined whether higher IR and fasting glucose were related to increased odds of tau PET positivity assessed using [F‐18]MK‐6240 positron emission tomography (PET). We also explored whether relationships to tau PET positivity were moderated by global amyloid pathology measured using [C‐11]PiB PET.MethodParticipants were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core (Table 1). In the IR study, n=231 WRAP participants had homeostatic model assessment of insulin resistance (HOMA2‐IR) and PET. Twenty‐eight (12.1%) were tau PET positive (entorhinal MK‐6240 SUVR > 1.27; Betthauser et al., 2020) and 59 (25.5%) were amyloid PET positive (global PiB DVR > 1.19; Racine et al., 2016). In the Glucose study, n=332 participants (n=239 WRAP; n=93 Wisconsin‐ADRC) had fasting glucose and PET. Forty‐nine (14.8%) exhibited tau PET positivity and 81 (24.4%) were amyloid PET positive. Binary logistic regression tested whether HOMA2‐IR and glucose were related to odds of tau PET positivity. Global PiB DVR was explored as a moderator of HOMA2‐IR and glucose in separate logistic regressions.ResultHOMA2‐IR and glucose were not significantly related to odds of tau PET positivity (ps > .37), controlling for age, sex and global PiB DVR (Figure 1). Higher global PiB DVR (standardized using cut‐point to center) was significantly related to greater odds of tau PET positivity [IR study: Exp(2.8), p < .001, 95%CI: 1.9‐4.1; Glucose study: Exp(3.1), p <.001, 95%CI: 2.3‐4.4]. Global PiB DVR was not a significant moderator of insulin or glucose (ps > .81; Figure 2).ConclusionHOMA2‐IR and glucose may not be related to tau pathology in cognitively unimpaired adults. The low proportion of participants who were tau PET positive likely limited the detection of significant interaction effects. Additional research is needed in samples with a greater proportion of diabetic and cognitively impaired participants to determine potential pathways linking IR and glucose to dementia.
Amphiphilic distyrylbenzene derivatives as potential therapeutic and imaging agents for the soluble amyloid‐β oligomers in Alzheimer’s disease
Authors: Mirica Liviu M 
Published: December 2021

AbstractBackgroundNew amphiphilic distyrylbenzene derivatives have been developed that target both the soluble Aβ oligomers and amyloid plaques in Alzheimer's disease (AD), as well as the extracellular p‐tau aggregates, Aβ‐mediated oxidative stress, and neuroinflammation.MethodWe have developed a novel amphiphilic distyrylbenzene derivative that exhibits high binding affinity for Aβ aggregates ‐ especially the Aβ oligomers, and a series of ex vivo and in vivo immunostaining and imaging studies were employed to probe the beneficial properties of this potential therapeutic agent.ResultUpon treatment of 5×FAD mice with an amphiphilic distyrylbenzene derivative, fluorescence imaging of the brain sections shows that this compound can easily penetrate the blood‐brain‐barrier and selectively bind to the Aβ oligomers, as confirmed by the colocalization with an Aβ oligomer‐specific antibody. Furthermore, when comparing the MFC‐treated mice vs. the vehicle‐treated mice, the total amount of Aβ species and the associated p‐tau aggregates was significantly decreased by up to 70%, along with a significant reduction in the amount of activated microglia.ConclusionThe amphiphilic distyrylbenzene compound reported herein can attenuate the formation of amyloid plaques and associated p‐tau aggregates, while also reducing the microglia‐mediated neuroinflammatory response, which is uncommon among the previously reported amyloid‐targeting chemical agents.
Metabolomics analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Karaman Ibrahim , Pinto Rui , Solomon Alina , Ngandu Tiia , Correia Goncalo , Dehghan Abbas , Tzoulaki Ioanna , Matthews Paul M. , Lewis Matthew , Kivipelto Miia , Elliott Paul 
Published: December 2021

AbstractBackgroundThe Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a randomized controlled trial that showed significant benefits on cognition for a 2‐year multidomain lifestyle intervention vs regular health advice in 1260 at‐risk older individuals from the general population. The aim of this study was to investigate the metabolic effects of the intervention and their association with cognitive outcomes.MethodWe acquired metabolomics data of blood plasma on two time points (baseline and 2 years) in a set of 1089 participants (547 intervention and 542 control). A multi‐technology platform consisting of using ultra‐high performance liquid chromatography ‐ mass spectrometry (UHPLC‐MS) and 1H nuclear magnetic resonance spectroscopy (NMR) was used to generate extensive measurement coverage of the metabolome. The data was acquired using both reversed‐phase chromatography (RPC) tailored for the retention and separation of both complex and neutral lipids and hydrophilic interaction liquid chromatography (HILIC) for the retention and separation of small polar metabolites. The UHPLC‐MS untargeted data contains a total of 10,825 metabolomic features, 1244 of them currently annotated. The NMR data contains measurements of both small and macromolecules, including 112 lipoprotein fractions (derived using Bruker lipoprotein subclass analysis: BI‐LISA). Data analysis was conducted using linear mixed models.ResultSeveral baseline metabolite levels had a statistically significant association with cognition. Results will also be presented from ongoing analyses to investigate intervention effects on change in metabolites.ConclusionComplex metabolomics analyses are new in the context of multidomain lifestyle dementia prevention trials. While causality is yet to be investigated further, some of the metabolite classes and pathways observed (e.g. sphingolipids) have been previously implicated in cognitive decline and neurological disorders, suggesting early interpretable leads in the rich dataset at hand.
Childhood and adulthood traumatic events differentially associate with cognitive aging among Black and White elders in the Health and Retirement Study
Authors: Zuelsdorff Megan , Sonnega Amanda , Byrd DeAnnah R , Norton Derek , Deng Xinyue , Turner Robert 
Published: December 2021

AbstractBackgroundModifiable sociocontextual factors powerfully shape ADRD risk, and demonstrably contribute to well‐established racial disparities in cognitive aging. Stressful experiences occurring across the lifespan associate with brain aging and poor cognitive outcomes. However, the importance of timing and even type of stressor remains understudied. We examined relationships between childhood and adulthood traumatic events and cognition among non‐Hispanic Black and White older adults in the Health and Retirement Study (HRS).MethodThe sample included non‐demented adults (N=5,725) aged 65+ with lifetime stress data and complete cognitive testing at the 2006/08, 2010/12, and/or 2014/16 waves. Trauma measures included childhood (0‐11), and adulthood (0‐7) traumatic event counts. Outcomes included global cognition, immediate recall, and delayed recall (Telephone Interview for Cognitive Status). Each exposure‐outcome pair was investigated in separate linear mixed effect models including baseline trauma count, a quadratic trauma term to test for non‐linear relationships, and subject‐specific random intercept. Omnibus Likelihood Ratio Tests (LRT) were conducted to determine if number of traumatic events associated overall with each cognitive outcome. The sample was stratified by race before analysis.ResultBlack participants (N=651) were younger and reported less formal education than White participants (N=5,074). Number of traumatic events in adulthood did not vary by race, but Black participants reported slightly fewer childhood traumas (Table 1) than Whites. Among Whites, childhood traumas associated with poorer global cognition scores but traumas in adulthood showed very modest positive associations across cognitive domains. Among Black participants, no association between childhood trauma and later‐life cognition was observed. A significant non‐linear term for traumatic events indicated cross‐domain cognitive detriment associated with high exposure to adulthood trauma (Table 2; Figure 1).ConclusionAverage exposure to traumas (eg., physical abuse, life‐threatening illness) was low, and in both Black and White older adults, some limited exposure to traumatic events during adulthood predicted modest cognitive benefit. Black HRS participants reporting many traumatic events during adulthood, but not childhood, showed dysfunction in global cognition and recall. Findings highlight importance of adverse events across the full life course, potential threshold effects and co‐occuring chronic stress conditions, and a need to identify resources that buffer impacts of trauma on biology and personal environment.