bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic characterization of a Puerto Rican Alzheimer disease cohort implicates convergent immune‐related pathways
Authors: Griswold Anthony J. , Gardner Olivia K. , Rajabli Farid , Hamilton‐Nelson Kara L. , Adams Larry D. , Rodriguez Vanessa C. , Mena Pedro Ramon , Whitehead Patrice L. , Hofmann Natalia K. , Garcia‐Serje Catherine , Silva‐Vergara Concepcion , Feliciano Nereida I. , Feliciano‐Astacio Briseida E. , Acosta Heriberto , Haines Jonathan L. , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: December 2020

AbstractBackgroundGenetic risk factors for Alzheimer disease (AD) demonstrate distinct effects across diverse ancestral populations. The ancestral heterogeneity (admixture) of Caribbean Hispanics from Puerto Rico (PR), makes studies of the PR population important in the discovery of ancestry‐specific factors in AD. To expand ongoing genomic investigations of AD in PR individuals, it is necessary to characterize functional downstream effects by studying gene expression and regulation. Here we characterized the differences in gene expression, splicing, and RNA editing of the protein coding transcriptome from peripheral blood in PR individuals. to identify case vs control differential expression, splicing, and RNA editing in this diverse population.MethodPoly‐A selected RNA was from peripheral whole blood of 76 PR individuals over the age of 65 (39 AD, 37 cognitively normal controls) was sequenced and analyzed with a standard bioinformatics pipeline. Differential expression between PR cases and controls was calculated using DESeq2, alternative splicing using LeafCutter software, and RNA editing with REDITools and linear models. All analyses were adjusted for sex, age, and sequencing coverage. For each analysis, pathway enrichment analysis of Gene Ontology Biological Processes and KEGG gene sets were used to identify underlying biological pathways.ResultA total of 761 genes (518 up‐regulated, 243 down‐regulated) were differentially expressed between PR AD and controls (adjusted p ≤ 0.05). At the transcript level, 561 genes had a significant (FDR ≤ 0.05) differential splicing event. We also identified 35,246 total RNA editing sites. While there was no significant difference globally, 422 sites in 159 genes showed nominally significant editing difference (p ≤ 0.05). These genes, isoforms, and RNA editing sites overlap little with previous investigations of the transcriptomes of Non‐Hispanic Whites and African‐American AD with only a few genes in common. However, pathway enrichment across all three PR transcriptomic analyses consistently reveals differences in both the adaptive and innate immune response pathways, consistent with other ancestries.ConclusionTranscriptomic analyses of diverse populations in AD, shows stark divergence at the single gene level. However, the convergence on immune molecular pathways suggest shared underlying disease etiology and the possibility of broad therapeutic options.
Blood–brain barrier permeability measured by contrast‐enhanced MRI in early Alzheimer’s disease
Authors: Preis Lukas , Cetindag Arda Can , Villringer Kersten , Fiebach Jochen B. , Peters Oliver 
Published: December 2020

AbstractBackgroundThe importance of vascular integrity in the context of neurodegeneration and specifically Alzheimer’s disease (AD) is increasingly recognized. It has been shown that Blood‐brain barrier (BBB) breakdown in the hippocampus correlates with functional impairment independent of AD pathology. The aim of this study is to investigate BBB permeability in early stages of the AD continuum including subjective cognitive decline (SCD).MethodStudy participants were characterized according to the appropriate research criteria and categorized as normal controls (NC), individuals with SCD and mild cognitive impairment due to AD (MCI‐AD). Besides a clinical and neuropsychological assessment, the participants underwent structural magnet resonance imaging (MRI), ApoE genotyping and lumbar puncture. AD pathology was examined in accordance to the ATN‐system. Dynamic contrast‐enhanced (DCE) MRI T1 mapping and Patlak analysis using Rocketship software were employed to assess BBB permeability changes.ResultSeventy‐one participants were included (NC = 18, SCD = 36, MCI‐AD = 17). The average age of the cohort was 75 years and the sample consisted of 41% females. The median MMSE scores were 30 for NC and SCD and 27 for the MCI‐AD group. Amyloid pathology, measured in the CSF, was detected in 11% of the NC group (n = 2), 58 % of SCD (n = 21) and 29% of MCI/AD (n = 5). Bilateral BBB dysfunction was identified in 44% of NC (n = 8), in 31% of SCD (n = 11) and 24% of MCI‐AD (n = 4), additionally unilateral BBB dysfunction has been identified in 22% of NC (n = 4), 25% of SCD (n = 9) and 41% of MCI‐AD (n = 7).ConclusionBy using DCE MRI T1 mapping a surprisingly high proportion of increased BBB permeability in the hippocampus can be detected across all groups. Detailed analyzes will reveal the impact of BBB permeability on cognitive function in SCD.
Do repeated ambulatory cognitive assessments enhance the relation between objective and subjective cognition in non‐demented community dwelling older adults? Results from the Einstein Aging Study
Authors: Rabin Laura , Mogle Jacqueline , Katz Mindy J. , Sliwinski Martin J. 
Published: December 2020

AbstractBackgroundAlthough subjective cognitive concerns are common in older adults and may portend progression to Alzheimer’s disease, the cross‐sectional relationship between subjective and objective cognition is inconsistent. Many studies report statistically significant, though weak, relations between self‐reported cognition and neuropsychological test scores among cognitively normal (CN) older adults and those with mild cognitive impairment (MCI). Others have failed to find an association or have found stronger associations between subjective cognition and psychosocial variables. We applied a novel approach to investigate the subjective‐objective cognition relation, using both conventional measures and daily assessments in ethnically/racially diverse older adults.MethodParticipants (n=229, mean age=76.97, 65% female, 50% White) completed in‐person neuropsychological tests and a paper‐and‐pencil questionnaire of change in cognitive functioning over 5 years. Additionally, for 14 days, they completed daily cognitive tasks and self‐reported their experience of cognitive difficulties via smartphones. Participants were classified as MCI (n=62) or CN (n=167) using Jak/Bondi criteria. We used correlational analyses (controlling for depression) to compare subjective/objective data stratified by cognitive status and logistic regression to examine associations with diagnosis.ResultIn MCI, there were statistically significant moderate associations (r=.34 to .38; p<.01) between daily diary self‐reported cognition (retrospective and prospective memory) and ambulatory assessments of processing speed and spatial memory, respectively (performance averaged over multiple trials, across days); there was no relationship with traditional neuropsychological tests. In CN, there were statistically significant, weak‐moderate associations between self‐report of decline in various cognitive domains and traditional tests of episodic memory and language (r=‐.22 to ‐.29; p<.01). Self‐reported cognition on daily diary but not questionnaire items was associated with group membership, controlling for age, education, sex, and general cognition (p<.05).ConclusionFor individuals with MCI, daily reports of cognitive difficulties were moderately aligned with performance on objective ambulatory cognitive assessments. By contrast, in those with intact cognition, there was modest correspondence between single‐occasion retrospective reporting of cognition and traditional neuropsychological tests. Notably, only daily subjective report items predicted MCI status at baseline. Results have implications for enhancing the accuracy of assessments, particularly for those with MCI, through the inclusion of daily measurements to capture features of cognition that may otherwise be missed.
Associations of brain connectivity with disease progression and cognitive dysfunction in autosomal‐dominant Alzheimer disease depend on imaging modality
Authors: Dicks Ellen , Vermunt Lisa , Tijms Betty M. , van Der Flier Wiesje , Barkhof Frederik , Tanenbaum Aaron , Strain Jeremy F. , Morris John C. , Bateman Randall J. , Benzinger Tammie L.S. , Gordon Brian A. ,   the Dominantly Inherited Alzheimer Network
Published: December 2020

AbstractBackgroundIn the early stages of Alzheimer disease (AD) brain connectivity becomes disrupted. Brain connectivity can be measured based on resting‐state fMRI, DTI and structural MRI (i.e., grey matter (GM) covariance). It currently remains unclear, whether the timepoint of brain connectivity disruptions and associations with cognitive dysfunction depend on the imaging modality used. Here, we investigated for each modality in autosomal‐dominant AD, at which time to estimated symptom onset (EYO) mutation carriers (MC) and non‐carriers (NC) start to diverge and their association with cognition.MethodFrom the Dominantly Inherited Alzheimer Network (DIAN) we included all individuals who had one resting‐state fMRI (n=205), DTI (n=68) and/or structural MRI scan (n=434) available. Preprocessing and analysis are described in Fig.1. We calculated the network measures clustering, path length and their normalized versions (i.e., gamma and lambda). For each modality we used Bayesian mixed effects models with EYO as predictor to determine the first timepoint in the disease process, at which MC and NC start to diverge. We additionally assessed in MC the relationship between network measures and cognitive function (MMSE and logical memory, delayed recall), correcting for age.ResultAcross the EYO, GM‐based network measures showed divergences between MC and NC starting ‐8.1 years before symptom onset, followed by fMRI‐based network measures 0.7 years after symptom onset (Fig.2). For DTI, we found no significant differences, but MC showed slightly decreased clustering values around ‐10 years before symptom onset compared to NC. Both GM‐ and DTI‐based network measures showed associations with the MMSE, with the strongest effects for lower MMSE with lower gamma (standardized β±SE(DTI)=0.44±0.04; standardized β±SE(GM)=0.59±0.06; all p<0.001). GM‐ and fMRI‐based network measures were associated with logical memory performance, with the strongest effects for worse performance with lower lambda in fMRI‐based networks (standardized β±SE=0.16±0.07; p<0.05) and lower gamma for GM‐based networks (standardized β±SE=0.49±0.06; p<0.001).ConclusionGM‐based network measures showed the earliest differences between mutation carriers and non‐carriers, followed by fMRI. GM‐based network measures were associated with MMSE and logical memory, DTI with MMSE and fMRI with logical memory. This suggests that different modalities may capture specific processes in AD. Grant: P50AG005681.
Development and piloting of a novel 15‐minute cognitive telephone (FACT) screen to diagnose mild cognitive impairment and dementia
Authors: Ellajosyula Ratnavalli , Narayanan Jwala , Ramanan Siddharth , Dev Nidhi 
Published: December 2020

AbstractBackgroundIt is crucial to follow up patients with mild cognitive impairment (MCI) and dementia. For persons unable to visit hospital for follow‐up, we designed a brief telephone‐screen, the fifteen‐minute assessment of cognition over the telephone (FACT). This was piloted for its ability to diagnose and differentiate patients with MCI and Alzheimer’s disease (AD).MethodThe FACT consists of 27 items categorized under attention and orientation, memory, language, and executive functions domains. Patients with MCI (n=40), AD (n=40) and healthy age and education matched volunteers (n=23) were administered the FACT a week after presentation and neuropsychological testing at the clinic. Performance on the Addenbrookes Cognitive Examination (ACE III) was used as a gold standard.ResultFACT correlated well with ACE III, the Pearson correlation coefficient was 0.82 (p = 0.00). The subcomponents of both tests also showed moderate to high correlations. The area under the ROC curve for FACT discriminating MCI from AD was 0.92 and MCI from healthy volunteers was 0.83.ConclusionThe novel telephone interview screen (FACT) was comparable to the ACE III in diagnosing and differentiating patients with MCI from AD. A mobile telephone usage is almost universal across India including poor, illiterate and rural population. Thus the use of FACT as a screening tool may be extended to population surveys, which are crucial in tackling dementia, a major health challenge in India.
Mitochondria‐targeted therapeutics restore cognitive function and halt progression of neuropathology in symptomatic AD mice
Authors: Stojakovic Andrea , Trushin Sergey , Chang Su‐Youne , Li Xing , Khalili Layla , Lee Michael K. , Trushina Eugenia 
Published: December 2020

AbstractBackgroundWe have previously demonstrated that partial reduction of mitochondrial complex I (MCI) activity using small molecules is efficacious in decreasing levels of amyloid beta (Aβ), phosphorylated Tau, augmenting mitochondrial bioenergetics, promoting resistance to oxidative stress and restoring mitochondrial axonal trafficking, levels of BDNF and synaptic proteins in pre‐symptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype compared to their untreated littermates.MethodIn the current study, we tested whether treatment with MCI inhibitors could halt the disease progression when treatment was administered to symptomatic APP/PS1 mice.ResultTreatment improved glucose tolerance, prevented body weight loss, and ameliorated systemic inflammation. Treatment improved glucose uptake in the brain measured using FDG‐PET imaging. Electrophysiological recording in hippocampus indicated that synaptic activity and LTP were restored in treated APP/PS1 mice. Data gathered using 3D electron microscopy reconstruction of dendrites in CA1 region of hippocampus showed that treatment increased the population of mature dendritic spines in APP/PS1 mice, which correlates with restored synaptic activity and improved glucose uptake and utilization in the brain. Immunohistochemical analysis showed that treated APP/PS1 mice had reduced brain level of Aβ plaques, markers of inflammation and reduced degeneration of TH+ neurons in locus coeruleus. The RNA‐seq gene function enrichment analysis showed that pathways down‐regulated by treatment with MCI inhibitors in APP/PS1 mice included the ones involved in oxidative stress and immune system response. Moreover, RNA‐seq data analysis depicted a cluster of genes involved in dendritic morphology, axonal guidance and neuronal development, which expression were reverted by treatment in APP/PS1 mice to the level observed in NTG mice. Western blot analysis in cortico‐hippocampal brain region of APP/PS1 mice confirmed that treatment increased signaling molecules involved in IGF‐1/insulin pathway, mitochondrial biogenesis, oxidative stress protection, autophagy and synaptic function.ConclusionOverall, our data suggest that long‐term treatment with MCI inhibitors is safe and efficacious in restoring cognitive function and preventing degeneration in symptomatic APP/PS1 mice. Therefore, partial MCI inhibitors represent a promising therapeutic approach to ameliorate AD and promote healthy aging.
Functional analysis of candidate genes identified through whole genome sequencing in Caribbean Hispanic families for late‐onset Alzheimer disease
Authors: Wang Liyong , Cukier Holly N. , Rajabli Farid , Hofmann Natalia K. , Adams Larry D. , Rodriguez Vanessa C. , Mena Pedro Ramon , Garcia‐Serje Catherine , Silva Concepcion , Feliciano Nereida I. , Feliciano‐Astacio Briseida E. , Acosta Heriberto , Vance Jeffery M. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: December 2020

AbstractBackgroundTo identify LOAD risk genes in Puerto Ricans (PR), a population underrepresented in genetic studies, linkage analysis of whole genome sequencing (WGS) in 23 multiplex PR families identified a peak on chromosome 9p21 (MLOD = 3.9). The 1‐LOD unit down region spans from 31∼38Mb; identity‐by‐descent (IBD) sharing region spans from 23‐39 Mb. Two genes in the linkage region, UNC13B, located in the center of the linkage peak (35.1∼35.4 Mb), and ELAVL2 (23.7∼23.8 Mb), at the edge of the IBD sharing region, are of interest. Both genes have multiple rare variants with low minor allele frequencies (MAF) and high CADD scores that segregate with LOAD in the families. UNC13B encodes a protein involved in Ca2+ release at the synapse, and calcium dysfunction has been associated with LOAD. ELAVL2 encodes a neural‐specific protein involved in RNA processing.MethodRecombinant plasmids for testing overexpression (UNC13B) and promoter activity (ELAVL2) were made by site‐directed mutagenesis and transfected into the neuronal SH‐SY5Y.ResultTwo UNC13B missense variants, rs35199210 (Asp238Glu, CADD = 22, MAF = 0.5%) or rs41276043 (Phe1096Leu, CADD = 26.5, MAF = 0.5%) have been cloned into overexpression vectors and are currently being evaluated for their effect on Ca2+ release rates. One promoter variant rs542037226 (CADD = 16.6, MAF = 0.03%) in the ELAVL2 demonstrated strong activity (∼200x higher than the empty vector), and the rare allele showed reduced activity compared to the reference allele (10% reduction, p = 0.03).ConclusionTwo potential new LOAD genes with rare variants have been identified within the linkage 9p21 linkage peak. Using segregation and in‐silico analysis we have prioritized rare variants in each gene for testing. Successful demonstration of functional changes in the ELAVL2 variants provide support for this approach. Evaluation of UNC13B variants are underway. Those variants with functional effects will be further evaluated in our inducible pluripotent stem cell models.
Blood‐cell‐based biomarker detection of Alzheimer’s disease
Authors: Cliff Richard O 
Published: December 2020

AbstractBackgroundThere is an urgent need for early screening diagnostics for Alzheimer’s disease (AD), cases continue to increase without effective diagnosis and treatment solutions. There is no test to diagnose AD at its earliest stages in healthy asymptomatic individuals to determine disease status. Fluid biomarkers, particularly blood‐based, could have the capacity to be widely implemented as diagnostic screens and to rule‐in/rule‐out further invasive and expensive testing. Amyloid‐beta (Aβ) oligomers continue to be a compelling target for therapeutics and diagnostics, are present in blood and are bound by blood cells. Given the accumulated evidence that Aβ oligomers are present in blood; we are developing a novel early detection blood cell‐based biomarker test using proprietary peptide ligands before any signs of AD in healthy asymptomatic individuals, much like a cholesterol blood test for cardiovascular disease.MethodOur technology, Pronucleon™ peptides, involves custom‐synthesized peptides that mimic the misfolding region of proteins such as Aβ. We’ve established specific, sensitive and selective detection of Aβ oligomers with our peptides using spectroscopic techniques. For this study we measured the binding capacity index (BCI) of blood cells using the following assay: diluted whole blood was incubated with or without our proprietary stabilized Aβ oligomer; fluorescently‐labeled Pronucleon™ peptide was then incubated with the blood samples followed by flow cytometric analysis. We compared the fluorescence intensity of each sample, one with and one without the stabilized Aβ oligomer. The assay was performed on 60 clinical samples (n=20 for each Control, MCI and AD) followed by statistical analysis to confirm any differences within and between the patient groups.ResultPronucleon™ peptides displayed specificity and sensitivity for Aβ oligomers; peptides also showed increased binding to AD blood cells as compared to normal; our cell‐based flow cytometry assay exhibited differentiation in BCI scoring between healthy and AD samples.ConclusionThese results set the stage for further development of an exciting innovative approach toward a screening tool for diagnosing Alzheimer’s disease, allowing the primary care setting in the medical community, the AD therapeutic community and the public an opportunity to address early detection of this disease before its symptoms appear.
A novel gut microbiome therapeutic derived from dietary polyphenols attenuates neuroinflammation in vivo in a model of c9orf72 mediated frontotemporal dementia
Authors: Trageser Kyle J. , Smith Chad , Estill Molly , Sebastian Maria , Pasinetti Giulio Maria 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative disorder with various genetic etiologies, the most prevalent of which include G4C2 expansions in the c9orf72 gene. Expansions produce dipeptide repeat proteins (DPR), forming aggregates with deleterious impacts on cellular processes and correlating with neuroinflammation. Glycine‐Arginine (GR) aggregates are the only significantly correlated DPR found in clinically relevant neuroanatomical regions of the brain. Our current study investigates the contribution of innate immunity to FTD pathogenesis and the attenuation of neuropathologies with the brain bioavailable microbiome‐derived metabolite, 3‐hydroxybenzoic acid (3‐HBA).MethodMice were transfected via intracerebroventricular injection with AAV9‐GFP(GR)100 or AAV9‐GFP and treated starting on Day 28 with either PBS vehicle or 50 mg kg‐1 of 3‐HBA. At 14 weeks mice were sacrificed and frontal cortex (FC), somatosensory cortex (CTX), and hippocampal (HP) tissue was dissected and prepared for RNA sequencing. Differentially expressed genes (DEGs) were identified using DESeq2 and pathway alterations were detected using Ingenuity Pathway Analysis. ELISA for IL‐1β was conducted on FC, CTX, and HP tissue. To determine the ability of 3‐HBA to reduce secretion of IL‐1β, primary microglia pretreated with 3‐HBA were stimulated with LPS+ATP and IL‐1β concentration was analyzed by ELISA.ResultDEGs associated with FTD pathology, protein expression levels of the pro‐inflammatory cytokine IL‐1β, and subsequent amelioration via treatment with 3‐HBA were demonstrated to be a result of contributions from the innate immune system and inflammasome activation in microglia. Inflammatory pathways differentially enriched among treatment groups include TREM1 Signaling, the complement system, and NFκB signaling. GR‐100 Vehicle treated animals exhibited elevated IL‐β in cortical tissue. 3‐HBA was efficacious in vivo in rescuing IL‐1β levels in GR‐100 HBA treated mice to levels of GFP animals. Primary microglia pretreated with 3‐HBA and stimulated with LPS+ATP significantly reduced IL‐1β release, signifying the efficacy of 3‐HBA in attenuating innate immune reactivity.ConclusionPathways and genes associated with the innate immune system show enrichment in a model of FTD and are rescued by administration of 3‐HBA. Overexpression of IL‐1β in the cortex of GR‐100 Vehicle animals is attenuated by the administration of 3‐HBA. Our data implicates a gut‐brain axis mechanism of treatment for key FTD associated neuropathologies.