bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma pTau181 is associated with impaired cognition in the Old Order Amish and adds additional information beyond the known genetic risk factors for AD
Authors: Prough Michael B. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Dorfsman Daniel A. , Adams Larry D. , Laux Renee A. , Song Yeunjoo E. , Lynn Audrey , Fuzzell M. Denise , Fuzzell Sarada L. , Miller Sherri D. , Miskimen Kristy L. , Main Leighanne R. , Osterman Michael D. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Scott William K. , Pericak‐Vance Margaret A. 
Published: December 2022

AbstractBackgroundAs plasma biomarker assays have become more widely available, they are increasingly being used to characterize AD and related dementias. The Old Order Amish are a cultural and genetic isolate in the US that have participated in genetic studies for decades. This study investigated plasma phosphorylated tau at threonine‐181 (pTau181) in an Old Order Amish cohort to determine if the association with cognitive status is reproducible in this population.MethodOld Order Amish individuals over age 65 (n=467, mean age = 81.3, 60.6% female) in Indiana and Ohio were examined using a modified Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery. Each individual was assigned Impaired (n=155, mean age = 82.5, 56.8% female) or Unimpaired (n=312, mean age = 80.8, 62.5% female) cognitive status via consensus review of these examination results. The level of plasma pTau181 was measured using the pTau181 Advantage V2 assay from Quanterix. Genetic Risk Scores (GRS) were calculated using genome‐wide significant variants from Kunkle et al. (2019), weighted by log odds ratio estimates. A t‐test was used to compare plasma pTau181 levels between the Impaired and Unimpaired groups. Logistic regression was then used to model the contribution of age, sex, GRS, and plasma pTau181 on cognitive status.ResultWe found that the average level of plasma pTau181 was significantly higher in the Impaired group (2.46 pg/mL) compared to the Unimpaired group (2.01 pg/mL) at p<0.0001. A multivariable model found increasing age (OR=1.10, p=0.0002), male sex (OR=1.60, p=0.04), increasing GRS (OR=1.97, p<0.0001), and increasing plasma pTau181 (OR=1.46, p=0.001) associated with impaired cognitive status. The effect of GRS is mostly attributable to APOE.ConclusionThe result of these analyses indicates that pTau181 is associated with impaired cognitive status in the Old Order Amish, adding additional information beyond the known genetic risk factors for AD.
Role of Vitamin D on cognitive performance among healthy volunteers of SANSCOG cohort
Authors: Lingegodwa Abhishek Mensegere , Giridhar Varsha , Bota Ragasudha , Ravindranath Vijayalakshmi 
Published: December 2022

AbstractBackgroundNutrients such as vitamin D play an important role in aging and dementia and evidence on the effect of vitamin D on cognition among healthy aging adults especially in rural India is sparse. Our aim was to observe the effect of vitamin D on cognition.MethodUsing a cross‐sectional study design we examined cognitive performance between vitamin D sufficient, vitamin D insufficient and vitamin D deficient groups among the cognitively healthy volunteers of SANSCOG cohort.ResultOur analysis revealed that two thirds (74.5%) had suboptimal vitamin D levels (Insufficiency: 38.3% and Deficiency: 36.2%) and women were more affected than men. Vitamin D levels affected subject’s depression scores and diabetes status negatively, however no effect was found on cognitive performance.ConclusionIt may be postulated that vitamin D plays an indirect role on cognitive performance. Large proportion of suboptimal vitamin D levels in the rural population warrants proactive public health measures.
Translational potential of JAX humanized APOE mice: Peripheral biomarkers of pathology
Authors: McLean John W. , Reyes‐Reyes Elsa M. , Bhattrai Avnish , Wiegand Jean‐Paul L. , Raikes Adam C. , Rodgers Kathleen E. , Brinton Roberta Diaz 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) drives the global rising incidence of neurodegenerative dementia. Disease progression includes cerebral aggregation of amyloid‐beta plaques and immune activation. Many AD animal models carry mutations that cause an early onset of these phenotypes, but the mutations are rare in human populations; most cases are idiopathic and late‐onset AD (LOAD). Another approach utilizing a transgenic APOE animal model may better model clinical populations. APOE4 is the predominant genetic risk factor for LOAD and confers increasing risk for LOAD in allelic fashion, relative to normative APOE3. This study investigates the JAX humanized APOE knock‐in mouse model of LOAD’s translational potential for peripheral biomarkers of pathology in aged, male and female mice.MethodAged mice of both sexes (23‐25 months old; 39M/37F) with APOE3/3,APOE3/4, andAPOE4/4 genotypes underwent blood plasma amyloid‐beta (Aß) measurement. A subset of these animals (30M/28F) additionally received peripheral immunophenotyping of whole blood via flow cytometry. Two‐way ANOVA and post‐hoc t‐tests were conducted to determine data significance.ResultsFemale mice had lower Aß42 plasma levels as well as a decreased Aß42/40 ratio, suggesting higher levels of the aggregate‐prone Aß42 protein in the brain, but there were no observed APOE genotype effects. Blood plasma Aß40 levels did not differ by genotype or sex. Whole blood flow cytometry showed an elevation in CD8+ memory T cells in APOE4/4 mice relative to APOE3/3 andAPOE3/4 mice. Aged female mice had a peripheral immune cell profile consistent with a more reactive and dysfunctional immune system than genotype‐matched aged males: higher levels of CD11b+ B cells, CD4+ helper T cells, and CD8+ cytotoxic T cells along with a lower percentage of naïve CD4+ and CD8+ T cells.ConclusionIn mice aged to resemble a ∼70‐year‐old human population, these results suggest increased brain levels of the aggregate‐prone Aß42 isoform and a reactive peripheral immune system in female APOE mice. This sex difference is consistent with the increased prevalence of LOAD in women. However, the specificity of APOE4 genotype effects may define the translational potential of this humanized APOE mouse model of late‐onset Alzheimer’s Disease.Research supported by T32AG061897, R01AG057931, and RF1AG059093 to RDB.
Differential properties of Early vs. Late 18F‐Florbetaben imaging acquisition time frames
Authors: Johnson Aubrey S. , Smith Anna C. , Tomljanovic Zeljko , Ziaggi Galen , Roetman Andrew E. , Klein Julia , Keegan Richard , Honig Lawrence S , Kreisl William Charles 
Published: December 2022

AbstractBackground18F‐Florbetaben (FBB) is a PET radioligand approved for determining binary amyloid status. According to the product label, FBB images may be acquired anytime 45‐130 minutes post injection. Protocols vary in the acquisition of FBB with respect to use of Early (50‐70 minutes‐post‐injection) or Late (90‐110 minutes‐post‐injection) frames. Identifying differences between Early and Late acquisitions of FBB data could aid in image interpretation and inform efforts towards harmonization across cohorts. We evaluated inter‐rater agreement of visual reads (VR) and differences in SUVR thresholds to characterize Early vs. Late frames.MethodFifty‐three subjects were studied including 23 patients meeting clinical criteria for amnestic mild cognitive impairment or mild Alzheimer’s disease and 30 cognitively normal controls. FBB images were acquired 50‐110 min post‐injection in 5‐min frames. Images were corrected for subject motion and separated into 50‐70 and 90‐110 min time windows. Three certified readers blind to cognitive status and time window provided a binary VR for each of the 106 data sets. Global standardized uptake value ratios (SUVRs) were calculated using a cerebellar gray matter reference. An ROC‐derived SUVR cut‐off value was determined for each window using a preliminary cohort (n=23) and evaluated in a larger cohort (n = 53).ResultInter‐reader agreement was similar in 50‐70 min and 90‐110 min scans, (Fleiss Kappa= 0.597 and 0.598). SUVRs from 50‐70 min and 90‐110 min scans were highly correlated (r = 0.99, p<0.0001). SUVRs were greater in visually positive than in visually negative scans for both time windows (Fig. 1; p<0.0001). SUVRs were still increasing at 50‐70 min but became but plateaued at 90 min. ROC‐derived SUVR cut‐off values (Fig. 1; SUVR50‐70=1.342, SUVR90‐110=1.524) largely agreed with the majority consensus VR (49/53; 92.5%) across both time frames.ConclusionEarly and Late frame data were highly correlated, and both provided robust quantitative differences between visually positive and negative Ab groups. However, imaging at 90‐110 min provides more stable SUVRs and therefore is preferred for measuring longitudinal change in amyloid burden.
Assessing periadolescent memory ability and characterizing the development of a functional brain network vulnerable to Alzheimer’s disease
Authors: Behm Lillian , Phipps Connor J , Ramirez Meghan K , Sexton Jennifer N , Heller Abi M , Zatkalik Abigail L , Nickolas Kristen , DeCesare Thomas A , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E 
Published: December 2022

AbstractBackgroundIn typically presenting Alzheimer’s disease (AD), pathological changes to the hippocampus (Hc) and its associated functional brain networks result in impaired declarative/relational memory. While it is known that risk factors for AD (genetic, environmental, etc.) can impact hippocampal resting‐state functional connectivity (RSFC) later in life, the development of the hippocampus and its connections to other brain regions may also be influenced by such risk factors. The goal the current study was to characterize the neurodevelopmental changes in this hippocampal network during the periadolescent epoch and determine whether the observed changes were associated with declarative/relational memory ability. Therefore, we utilized a cross‐sectional approach to test whether individual differences in hippocampal RSFC covary with outcomes on a test of relational memory ability in periadolescent children.MethodData were drawn from an ongoing NIA‐funded project: the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. Our analysis was carried out using data from healthy periadolescent participants (N=90; age 8‐13 years). We assessed declarative/relational memory with Cambridge Cognition’s Paired Associates Learning (PAL) task. To conduct the resting‐state functional MRI analyses, we used a seed‐based approach with the bilateral hippocampus as the seed region of interest. We then analyzed the hippocampal RSFC data to and assessed covariance of individual patterns of hippocampal RSFC with memory performance measured with the PAL task.ResultOur preliminary findings, largely consistent with previous work, demonstrate patterns of hippocampal RSFC sharing territory with the ventral and lateral portions of the default mode network (DMN). In addition, we observed evidence of regional covariance between hippocampal RSFC and PAL task performance.ConclusionThe preliminary findings of the ongoing PRANK study indicate that hippocampal RSFC covaries regionally with hippocampal‐dependent memory ability in periadolescent children. Future work from the PRANK study aims to understand whether genetic and polygenic risk factors for AD influence this hippocampal network development. To do so, we will utilize participants’ AD polygenic risk scores, and determine whether those scores are related to individual differences in hippocampal RSFC.
Antisense oligonucleotides targeting miR‐29b binding site increase translation of progranulin protein: potential therapeutic strategy for progranulin‐deficient frontotemporal dementia
Authors: Aggarwal Geetika , Banerjee Subhashis , Jones Spencer A. , Pavlack Monica , Benchaar Yousri , Bélanger Jasmine , Sévigny Myriam , Smith Denise M. , Niehoff Michael L. , de Vera Ian Mitchelle S. , Petkau Terri L. , Leavitt Blair R. , Ling Karen , Jafar‐nejad Paymaan , Rigo Frank , Morley John E. , Farr Susan A. , Dutchak Paul A. , Sephton Chantelle F. , Nguyen Andrew D. 
Published: December 2022

AbstractBackground
GRN mutations cause frontotemporal dementia (FTD) due to haploinsufficiency of progranulin. Several microRNAs (miRs), including miR‐29b, have been reported to negatively regulate progranulin protein levels. Here, we tested if antisense oligonucleotides (ASOs) – which are versatile modulators of target mRNA/protein levels – can be used to increase progranulin levels by sterically blocking the miR‐29b binding site.MethodWe designed 48 ASOs targeting the miR‐29b binding site in the 3’ UTR of the human GRN mRNA. We treated H4 neuroglioma cells and iPSC‐derived neurons with these ASOs and subsequently measured progranulin protein levels by western blot and ELISA. We performed further studies to determine the mechanism of action of these ASOs using ribosomal profiling, metabolic labeling, and FRET assays.ResultsWe identified 16 ASOs that increased progranulin protein levels in a dose‐dependent manner. Ribosomal profiling experiments revealed that cells treated with ASOs had marked enrichment in GRN mRNA in heavy polyribosome fractions, compared to cells treated with a scrambled control ASO, suggesting that the ASOs increase the rate of progranulin translation. Consistent with this, ASO treatment resulted in increased levels of newly synthesized progranulin protein. FRET‐based assays showed that ASOs can effectively compete miR‐29b from its binding site in the GRN 3’ UTR RNA under in vitro conditions.ConclusionsTogether, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This strategy may be therapeutically feasible for progranulin‐deficient FTD as well as other conditions of haploinsufficiency.
Non‐invasive quantification and SUVR validation of [18F]‐florbetaben with total‐body EXPLORER PET
Authors: Holy Emily Nicole , Fan Audrey P. , Alfaro Evelyn Rebekha , Fletcher Evan , Spencer Benjamin A. , Cherry Simon R. , DeCarli Charles S. 
Published: December 2022

AbstractBackgroundKinetic modeling of brain amyloid deposition with [18F]‐florbetaben more accurately quantifies the binding density to amyloid plaques compared to standardized uptake ratios (SUVR) (Becker, JNM2013). The total‐body EXPLORER PET scanner with an axial field of view of 194cm supports the acquisition of a full human body in one scan and permits noninvasive Image‐Derived Input Functions (IDIFs) as an alternative to arterial blood sampling (Badawi, JNM 2019). Our aim is to quantify amyloid buildup with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and validate with SUVR in an elderly cohort.MethodTwelve adults aged 66‐86 underwent dynamic total‐body 18F‐florbetaben PET for 110min, spatial resolution = 2.344mm, average tracer dose = 299.70 MBq. 8 cognitively‐normal, 3 Mild Cognitive Impairment (MCI), and 1 Alzheimer’s disease (AD). Regions of interests were drawn in the middle descending aorta and eroded to exclude the vessel walls to derive IDIFs (Fig.1). Next, regional brain analysis including PET image matching to previously acquired T1‐weighted MRI, normalization, and segmentation were performed in PMOD (v4.2) using the AAL atlas. PET SUVR (90‐110min) means were calculated from 7 index regions (lateral frontal, medial frontal, anterior cingulate, posterior cingulate, lateral temporal, lateral parietal, and precuneus) and the cerebellar gray matter. Dynamic time activity curves (TACs) from the same brain regions were fit to the two‐tissue compartment model (2TCM) using population metabolite‐corrected IDIFs; and the Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).ResultAmyloid‐positive patients showed the highest SUVR in brain index regions (Fig.2). High quality dynamic kinetic modeling was achieved (Fig.3), with high SUVR accumulation in index regions compared to cerebellum at later time points in amyloid‐positive cases. SUVR and DVR from kinetic models were strongly correlated; with slight overestimation of SUVR compared to DVR (Fig.4). DVR values from the MRTM were lower than (86.7% of) DVR quantified by 2TCM.ConclusionAbsolute quantification of amyloid binding from total‐body [18F]‐florbetaben PET data is feasible using aorta IDIFs with high agreement between dynamic binding parameters compared to SUVR in discriminating positive and negative scans.
Fine‐mapping of chromosome 9p21 linkage in Puerto Rican Alzheimer disease families.
Authors: Celis Katrina , Rajabli Farid , Simon Shaina A , Wang Liyong , Hamilton‐Nelson Kara L. , Adams Larry D. , Mena Pedro Ramon , Whitehead Patrice L. , Van Booven Derek , Feliciano‐Astacio Briseida E. , Chinea Angel , Feliciano Nereida I , Acosta Heriberto , Dalgard Clifton L. , Haines Jonathan L. , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. 
Published: December 2022

AbstractBackgroundWe previously reported strong linkage on chromosome 9p21 in multiplex Alzheimer disease (AD) families from Puerto Rico. Nine families had the highest linkage contribution. 3/9 families shared seven coding variants with displayed evidence for AD association in similar ancestral. Although these variants reside in genes with neuronal expression and functionality, they do not explain the linkage signal in all families. Here, we performed a fine‐mapping analysis to identify non‐coding variants that can contribute to the AD trait previously observed.MethodWe analyzed whole genome sequencing (WGS) from 9 families, 43 AD and 15 cognitively intact individuals. Chromatin interaction and cis‐regulatory element (CREs) were used to prioritized relevant non‐coding variants. Induced pluripotent stem cells (iPSC) derived neurons were generated from five individuals for characterization.ResultWe found an average of 300,000 non‐coding variants per family. Following filtering steps including segregation, allele frequency and chromatin association, we identified ∼400 variants per family. These variants were analyzed using the CREs derived from ENCODE, which left us with 31 (8%) variants falling in promoters. 5/31 variants were shared among four or more families, and fall in the promoter of genes FBXO10, ACO1, NDUFB6 and DNAJA1. Six families shared variants in FBXO10 making it our top candidate gene, a F‐box protein family with a role in apoptosis and immunity. Interestingly, another F‐box protein (FBXL7) has been associated with AD in a Caribbean Hispanic population.ConclusionThese results reiterate the importance of family‐based studies and fine‐mapping as a resourceful tool to identified functional variants in AD. Transcriptomic profile and functional characterization of iPSC derived neurons will aid to understand the implication of prioritized genes in the linkage association previously observed.
Identifying context‐specific genetic variants and molecular pathways associated with resilience to Alzheimer’s disease in the induced immune response
Authors: Mustafa Yousef , Naj Adam C. , Bush William S. , Below Jennifer 
Published: December 2022

AbstractBackgroundNeurodegenerative pathologies consistent with Alzheimer’s disease (AD) are common in older adults even among those without cognitive symptoms. Genome‐wide association studies (GWAS) have identified loci associated with better‐than‐predicted cognitive performance for a given level of neuropathology, described as resilience to AD symptoms. Transcriptome‐wide association studies (TWAS) provide powerful mechanistic insights bridging the association between loci and phenotype by implicating genes. We hypothesize that genetic variants influence resilience phenotypes by altering the function and response of monocytes, one of the premier immune cells involved in neuroinflammation. Moving to test this hypothesis, we have developed monocyte TWAS reference panels based on expression from a naïve state and following in vitro stimulations which can reveal important associations only seen in an inflammatory context.MethodsGenetic data of monocytes produced by Fairfax et. al 2014 were obtained and SNPs imputed on the Michigan Imputation Server using samples available on the Haplotype Reference Consortium. Plink 1.9 was used for standard quality control. Corresponding monocyte expression data was downloaded from ArrayExpress, and a custom script was used to extract probes not overlapping with regions containing common SNPs (MAF > 0.05) and mapping to single genes. Cis‐eQTL analysis was then performed using the MatrixeQTL R package, and final gene expression prediction panels constructed by fitting elastic‐net regularized regression models using the PredictDB pipeline.ResultsOur pipeline has been validated through showing concordance between our results and those of the Fairfax group with respect to the rs1179625 SNP and its context‐specific direction of effect on the gene expression of HIP1. Further, genotype imputation enabled the identification of thousands of additional eQTLs and response‐eQTL’s (re‐eQTL’s) across the genome—illustrating the importance of studying these cells in an appropriate environment. TWAS analyses of their collective impact on resilience phenotypes are ongoing.ConclusionWe expand the available tissues and cell types for TWAS of AD by generating reference panels that account for the dynamic biology of monocytes in different states. These panels enable analyses that may have specific importance for cognitive resilience, and may provide concrete biological mechanisms as to how some individuals can manifest the neuropathology of AD and yet remain asymptomatic.
Association of Retinal Nerve Fiber Layer Thickness with Plasma pTau181 and Aβ42/Aβ40 ratio
Authors: Mathew Sunu , WuDunn Darrell , Mackay Devin , Dage Jeffrey L. , Russ Kristen A , Blennow Kaj , Zetterberg Henrik , Vosmeier Aaron , Tallman Eileen F. , Deardorff Rachael , Harris Alon , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L. 
Published: December 2022

AbstractBackgroundThe eye has been considered a ‘window to the brain’ and to several neurodegenerative brain disorders including Alzheimer’s disease (AD) that display alterations in the eye, especially the retina. Plasma levels of AD biomarkers, including pTau181 and Aβ42/Aβ40 ratio are significantly altered in AD patients. We sought to evaluate the association of peripapillary retinal nerve fiber layer (RNFL) thickness measured using optical coherence tomography (OCT) with plasma levels of pTau181 and the Aβ42/Aβ40 ratio.MethodParticipants (78; 21 mild cognitive decline/AD, 27 subjective cognitive decline and 30 cognitively normal) underwent ophthalmological evaluation including OCT and a blood sample. Single molecule array (Simoa) assays were used to measure plasma concentrations of pTau181, Aβ42, and Aβ40 at the University of Gothenburg. Partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary retinal nerve fiber layer (RNFL) with plasma level of pTau181 and the ratio of Aβ42/Aβ40.ResultPlasma pTau181 was significantly associated with RNFL thickness in the superior quadrant of the retina in the right eye (rp=‐0.300, p=0.025) and showed a trend towards an association with mean RNFL thickness of the right eye (rp= ‐0.226, p=0.094). Plasma Aβ42/Aβ40 showed a significant positive association with nasal RNFL of the right eye (r=0.312, p=0.027), as well as a negative association with RNFL thickness in the temporal quadrant of both eyes (right: r=‐0.324, p=0.022; left r=‐0.325, p=0.021).ConclusionThe majority of the sample was cognitively normal or mildly impaired, suggesting that RNFL thickness may be a useful tool for early diagnosis of AD‐related pathophysiology. Future longitudinal studies in larger samples and evaluating the utility of combining retinal and plasma biomarkers for predicting future progression to AD are needed.