bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding the role of amyloid on cerebral microvasculature in Alzheimer’s disease: A pre‐clinical Intra Voxel Incoherent Motion (IVIM) study
Authors: Shahid Syed Salman , Yen Jui‐Hung , Paraiso Hallel C , Wu Yu‐Chien , Yu Ivorine 
Published: December 2022

AbstractBackgroundVascular perturbation is emerging as an important contribution to Alzheimer’s disease (AD) trajectory. However, the role of microvascular alterations in pathophysiological processes remains unclear. We hypothesized a direct link between β‐amyloid (Aβ) and the cerebral microvasculature, leading to vascular stress, deteriorated blood‐brain barrier, and impaired microcirculation. The early detection of changes in the microvasculature can be used as an early biomarker to study underlying disease mechanisms. This study used intra‐voxel incoherent motion (IVIM) technique to quantitatively map functional capillaries related to blood volume fraction as surrogate marker for microvasculature alterations in an Alzheimer’s disease mouse model.MethodMale 5xFAD mice at 6‐months‐old and age‐matched littermates were scanned using high‐resolution IVIM optimized DWI. The DWI and anatomical images were acquired on a horizontal bore 9.4T Biospec micro‐MRI system equipped with a 1H cryogenic coil. 2D T2‐weightd images were acquired with a voxel size of 60x60x300 µm3 and DWIs were acquired with a voxel size of 120x120x300 µm3. Hippocampal subfields (CA1, CA2, CA3, DG, and Subiculum) in (Badhwar hippocampal) atlas space were transformed to individual T2W space and then linearly transformed to DWI space. IVIM maps (Apparent diffusion coefficient [D], pseudo‐diffusion coefficient [D*], and perfusion fraction [fIVIM]) were calculated (voxel‐wise) using a bi‐exponential IVIM model. The mean fIVIM of individual subfields were used for group‐wise comparison, and the Hedges’g were used for effect‐size analysis.ResultOur preliminary results showed regional differences in microvascular perfusion fraction between control (n=6) and 5xFAD (n=8) mice at 6 months of age. fIVIM was significantly lower in DG (p<0.05; Hedge’s g =‐1.4; 95% CI: ‐2.552, ‐0.202) and in Subiculum (p<0.05; Hedge’s g=‐1.3; 95% CI: ‐2.54, ‐0.194) of 5xFAD compared to wild‐type mice. The fIVIM remains unchanged in other subfields. The decreased fIVIM suggested that deficits in the capillary network of DG and Subiculum develop earlyConclusionThese findings support the sensitivity of IVIM to detect circulatory deficits in the hippocampal microvasculature associated with Aβ pathology. The IVIM may provide new insight into cerebral small vessel health in an early AD stage without a contrast agent administration and can be readily translated to the clinic.
Influence of fecal microbiota transplantation on gut microbiota composition in transgenic mice modeling amyloid‐β plaques and neurofibrillary tangles
Authors: Borsom Emily M , Keefe Christopher R , Hirsch Allyson H , Conn Kathryn A , Orsini Gabrielle M , Jaramillo Sierra A , Bolyen Evan K , Dillon Matthew R , Lee Keehoon , Caporaso J. Gregory , Cope Emily K 
Published: December 2022

AbstractBackgroundThe gut microbiota, the aggregates of all microbial cells that inhabit the gut, bidirectionally communicates with the brain through cytokines, hormones, metabolites, and neurotransmitters via the gut microbiota‐brain axis. The gut microbiota is thought to contribute to the development of Alzheimer’s disease (AD), which is characterized by plaque deposition, neurofibrillary tangles, and neuroinflammation. We hypothesize that manipulation of the gut microbiota will alter development of AD pathologies and neuroinflammation via the gut microbiota‐brain axis.MethodWe performed fecal microbiota transplants (FMT) from aged (52‐64 weeks) 3xTg‐AD mice, which are modeling plaques and neurofibrillary tangles, to young 3xTg‐AD (n=5) or wild‐type mice (n=10) via oral gavage. Phosphate buffered saline (PBS) was gavaged into 3xTg‐AD (n=5) and wild‐type mice (n=10) as a control. At 8 weeks, mice were gavaged with FMT or PBS for 5 consecutive days, followed by fortnightly maintenance transplants for 24 weeks. The V4 region of the 16S rRNA gene was sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. Reverse transcriptase qPCR was used to assess microgliosis, astrocytosis, and Th1/Th2 inflammation in the hippocampus of the FMT cohort at 24 weeks of age.ResultWe observed a shift in microbiota composition of FMT‐treated mice when compared to control (PBS‐treated) mice. Bacteroides acidifaciens was increased in 3xTg‐AD and wild‐type mice receiving FMT. We demonstrate partial engraftment of the gut microbiota from aged 3xTg‐AD mice in all FMT‐treated mice, demonstrated by a Random Forest model, which correctly predicts treatment groups based on gut microbiota composition (Accuracy Ratio over baseline assignment: 2.6).ConclusionWe demonstrate the ability to transplant an aged gut microbiome into young mice. Future shallow shotgun metagenomic sequencing will be used to determine the species‐ and strains‐ that engraft in the GI tract. Additionally, targeted reverse transcription RT‐qPCR and immunostaining for plaques and hyperphosphorylated tau in the hippocampus will be used to assess how FMTs alter AD pathologies. These studies will contribute to our understanding of how features of the gut microbiota may contribute to AD development.
Enhancing Sensitivity of Immunomagnetic Detection of Alzheimer’s Disease Biomarkers with Magnetic Nanoparticles and Anti‐Biofouling Coating
Authors: Li Yuancheng , Mao Hui 
Published: December 2022

AbstractBackgroundImmunomagnetic capturing/detection of biomarkers, including immunoprecipitation‐mass‐spectrometry (IP‐MS) and single molecule array (Simoa®), is a key technology in biofluidic‐based in vitro diagnosis of Alzheimer’s disease (AD). However, proteins and other biomolecules in samples can non‐specifically absorb on the surface of biomarker‐targeting ligand functionalized capturing agents, such as commercial magnetic beads (Dynabeads®). Such “biofouling” effect leads to the formation of a “protein corona” that not only attenuates the detection specificity, sensitivity and reproducibility by blocking the binding of targeted biomarkers, but also creates strong “contaminating” background signals. This report introduces a polyethylene glycol‐block‐allyl glycidyl ether (PEG‐b‐AGE) polymer coated magnetic iron oxide nanoparticle (IONP) rendering anti‐biofouling capability to improve the sensitivity of blood‐sample‐based AD biomarker detection.MethodNon‐specifically adsorbed proteins on Dynabeads® and anti‐biofouling IONP after incubating with human serum were quantified to evaluate biofouling effect. Dynabeads® and IONP were conjugated with antibodies, and compared for the detection of fluorescent dye FITC‐labeled AD biomarkers spiked in human serum (10 to 2000 pg/mL), including Aβ40, Aβ42, and phosphorylated tau (p‐tau181), which were quantified by fluorescence. To compare the detection in the settings of current platforms, spiked Aβ40 and Aβ42 in human serum were measured by IP‐MS using antibody‐conjugated Dynabeads® and IONP as the capturing agents. Antibodies in assay kits of Simoa® were used to conjugated with Dynabeads® and IONP to compare the detection of five AD biomarkers spiked in human serum in the Simoa® setting. Additionally, plasma samples from 21 AD patients were tested for Aβ40 and Aβ42 measurement using antibody‐conjugated IONP and Dynabeads® by IP‐MS.ResultAnti‐biofouling IONP demonstrated a ∼20‐fold reduction in serum protein adsorption, comparing to Dynabeads®. Dynabeads® and IONP demonstrated comparable detection sensitivity (captured/spiked, %) when spiked AD biomarkers at the concentration of ∼200‐2000 pg/mL. However, in samples with spiked AD biomarkers at ∼10‐100 pg/mL, Dynabeads® showed a decreased sensitivity up to 29% comparing to IONP. When Aβ40 and Aβ42 in patient plasma samples were immunoprecipitated by IONP or Dynabeads and analyzed by mass‐spectrometry, IONP showed 1.8‐ to 23.5‐folds greater signal‐to‐noise ratio (peak intensity/baseline) than Dynabeads®.ConclusionAnti‐biofouling IONP demonstrated improved sensitivity in blood‐based AD biomarker detections over Dynabeads®.
M2 microglia activation and proNGF inhibition : Possible Mechanisms Behind Cognitive Improvements by Low‐Dose Ionizing Radiation on Alzheimer's Disease; A Literature Review
Authors: Alifa Hasna Noor 
Published: December 2022

AbstractBackgroundRecent studies showed that Low‐Dose Ionizing Radiation (LDIR) may induce significant cognitive improvements on Alzheimer's disease (AD). The mechanism behind it is still remain unclear.MethodIn this review, numerous research papers and clinical studies results from the last 10 years related to LDIR exposure on AD as a treatment, immunochemistry in AD, and neurogenesis are collected. The results of the studies are then comprehensively analyzed to find any associations that could explain or give clues on how LDIR exposure may induce significant cognitive improvements in AD.ResultThere is evidence that LDIR modulates microglia phenotypes by switching phenotype M1 to M2. The anti‐inflammatory M2 microglia may associated in amyloid plaques and tau tangles reduction that showed in many studies on LDIR for AD treatment. Further study shows that LDIR also promotes proNGF inhibition that may triggers neurogenesis.ConclusionLDIR shows that it may be a promising novel treatment for AD retrospectively via immunomodulation and triggers neurogenesis.
Beta‐amyloid regions related to amyloid positivity using a feature selection method.
Authors: Ko Hyunwoong 
Published: December 2022

AbstractBackgroundCerebral beta‐amyloid (Aβ) is a hallmark of AD. Few studies have revealed which of the regional Aβ markers are associated with abnormal levels of Aβ status. The aim of the current study was to identify multivariate regional Aβ markers predicting Aβ positivity (Aβ+).MethodSeven hundred and sixty‐five participants from the ADNI‐2 cohort at baseline visit were included in the study. We used regional Aβ uptake as predictors in a predictive model. Flobetapir PET images were classified as Aβ‐positive if the standard uptake value ratio was over 1.1. The least absolute shrinkage and selection operator (LASSO) model with 1,000 bootstrap was implemented to identify regional Aβ traits to predict cortical amyloid burden from participants.ResultOut of 116 predictors, 27 markers in cortical thickness significantly predicted Aβ+ among participants at baseline. After bootstrapping, 2 phenotypes had 95% confidence intervals that did not overlap zero: left precuneus (β = 0.684) and right rostral middle frontal region (β = 0.605).ConclusionThese results demonstrated that several brain regions are related to abnormal levels of cerebral Aβ. These markers suggest robust sign that may capture AD pathology. To this end, this research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program (IITP‐2022‐2017‐0‐01630) supervised by the IITP (Institute for Information & communications Technology Promotion).
Metacognition in older African American adults during the COVID‐19 pandemic
Authors: Kero Katherine , Woodard John L. , Giordani Bruno , Daugherty Ana M. , Shair Sarah , Hanna Sophie , DiCerbo Loraine M. , Kavcic Voyko 
Published: December 2022

AbstractBackgroundThere is a critical need to identify older adults in the earliest stages of cognitive decline for targeted dementia reduction interventions. Subjective memory concerns often drive older adults to seek objective memory assessments. However, there is often poor agreement between subjective complaints and objective measures. Previous research suggests that self‐appraised memory decline may be more sensitive to mild cognitive impairment than objective measures, but factors influencing the relationship between self‐perceived and actual functioning are unclear. Subjective memory appraisal may be susceptible to negative affective perceptions such as anxiety. Anxiety has increased substantially during the pandemic, suggesting the heightened potential for it to distort subjective perceptions, thereby increasing demands for cognitive assessments. This study investigated whether the discrepancy between subjective cognitive concerns and objective cognitive performance is related to anxiety in a sample of older African American adults.MethodTelephone screenings were administered to 206 older African Americans (aged 64‐94 years) during the first year of the pandemic as part of a more extensive study. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS]), subjective memory (Cognitive Change Questionnaire [CCQ]), and anxiety (Generalized Anxiety Disorder‐7 [GAD‐7]) were measured, along with survey questions about affective and stress responses to COVID‐19 experiences.ResultObjective TICS scores were predictive of subjective CCQ executive function scores (F(1, 197) = 4.37, p = .038, R2 = .022). Discrepancy scores were calculated as the standardized residual variance between objective and subjective measures. Discrepancy scores were correlated with anxiety (r = .396, p<.001), indicating that higher anxiety was related to an overestimation of cognitive difficulty relative to the level of objective cognitive resources.ConclusionObjective and subjective measures of cognition are related. However, discrepancies exist between objectively‐measured and self‐perceived cognition. Elevation in anxiety level is associated with greater overestimation of cognitive difficulties relative to one’s objective level of cognition. As pandemic‐related stressors have worsened anxiety for some, individuals with higher anxiety may also have depreciated their self‐appraisal of cognitive abilities in the present climate. Clinicians should consider anxiety as a possible contributing factor when assessing subjective cognitive difficulties.
A decade of gene discovery by the Alzheimer’s Disease Sequencing Project
Authors: Schellenberg Gerard D. , Blue Elizabeth E ,   Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is caused in part by variation in genes and genetic regulatory elements. Early work identified autosomal dominant mutations in APP, PSEN1 and PSEN2 that cause AD, and large effect size variants in APOE. However, most of AD genetic risk is caused by variants that result in a modest change in risk. These variants are spread across many genetic elements. In 2009, genome‐wide association studies (GWAS) began to identify these AD loci (> 60 sites). While these studies continue to be productive, GWAS lacks the resolution to identify the critical AD genes and causative variants responsible for risk/protective signals. In 2012, the Alzheimer’s Disease Sequencing Project (ADSP) was initiated to use Next Generation Sequencing methods for AD gene discovery. Sequence data has single nucleotide resolution with the potential to identify causative common and rare variants and to detect structural variants (SVs; insertions, deletions, copy number variation, etc.).MethodThe ADSP is a collaborative network of investigators that assembles cohorts for sequencing, processes the data, and performs genetic analysis. In the past 10 years, the ADSP generated whole exome (WES) and whole‐genome‐sequence (WGS) data for 20,504 case and 43,004 control subjects. Subjects sequenced are or clinically diagnosed or neuropathologically confirmed AD cases and cognitively normal elderly subjects. Subjects include non‐Hispanic whites, Hispanics, African Americans, and Asians. In progress are WGS data for an additional ∼20,000 subjects. Sequence data are harmonized by the Genome Center for Alzheimer Disease and shared with the research community via the National Institute on Aging Genetics Data Storage site.ResultAnalysis of WES and WGS data nominates 46 AD genes and regions of interest (PMID: 35005195). These genes implicate known and novel AD pathways providing new insight into AD pathogenesis and novel therapeutic targets. SVs were detected in ABCA7 and NCK2. The ADSP includes functional genomics studies to connect risk variants to specific genes and to understand the function of these variants. Analysis methods also includes artificial intelligence/machine learning approaches.ConclusionThe genes and pathways identified by the ADSP are a rich source of validated targets for future therapeutic development.
Genetic Insights from the ADSP into Drug Discovery In Alzheimer’s Disease
Authors: Goate Alison , George‐Hyslop Peter St ,   Alzheimer’s Disease Sequencing Project
Published: December 2022

AbstractBackgroundA major goal of the NAPA plan initiated in 2013 is the development of novel drugs for the treatment and prevention of Alzheimer’s disease (AD). It is widely recognized that drug targets with genetic support are more likely to successfully make it through the drug development pipeline than those without genetic support. The target may be a genetic risk factor for AD or within a genetically regulated network implicated by an AD genetic risk factor. Thus, one of the primary goals of the Alzheimer’s disease sequencing project (ADSP) is to identify and validate putative novel drug targets and to work with the community to advance testing of these candidates.MethodsSince 2013 the ADSP has performed genome wide association studies of both common and rare variants to identify novel AD risk genes in diverse human populations.ResultsGenomic analyses have demonstrated that these AD risk alleles are enriched with regulatory regions, in microglial enhancers and the PU.1 regulatory network. The ADSP has also made a major effort in including different ancestries into AD research and utilized the differences in AD risk between ancestries for major genetic risk factors (like ApoE) to identified potential therapeutic targets. A key challenge for common variants associated with AD is to link them to specific genes, and to understand the subsequent biological processes that lead to AD. This is a major focus of the Functional Genetics Consortium within the ADSP. Rare coding variants have directly implicated specific genes, which also provide support for the central role of microglial function in AD risk, e.g. Trem2, ABI3, PLCg2. The genetics of endophenotypes (e.g. sTrem2) and of protein quantitative trait loci offer alternative approaches to link genetics to biology.ConclusionsTogether, common and rare variants identify myeloid cell efferocytosis as a key disease risk hub. An alternative approach to drug discovery is the use of in silico approaches to match disease relevant signatures to existing drugs to enable drug repurposing. To date this approach has focused on transcriptomic signatures and implicates several biological pathways including the integrated stress response.
PIB‐PET perfusion and FDG‐PET are highly correlated and similarly associated with cognitive performance
Authors: LaPoint Molly R. , Baker Suzanne L. , Landau Susan M. , La Joie Renaud , Rabinovici Gil D. , Jagust William J. 
Published: December 2022

AbstractBackgroundFluorodeoxyglucose PET is a useful measure of neurodegeneration in Alzheimer’s disease and aging. Because glucose metabolism and cerebral blood flow are coupled, PET measures of perfusion also detect neurodegeneration. Dynamic PET data obtained immediately following injection of highly extracted tracers can estimate relative perfusion (R1). We performed this study to examine R1 in relation to FDG PET for detection of AD and relationships to cognition.MethodDynamic Pittsburgh compound B (PIB) PET (0‐90 min) and FDG‐PET (30‐60 min) scans were collected in cognitively normal (CN) participants (N=109, mean age 76.2±6.4 years) and Aβ‐positive patients with MCI or dementia (N=85, mean age 65.1±9.6 years). The Simplified Reference Tissue Model 2 estimated R1 and PIB distribution volume ratios, the latter used to dichotomize CN participants by amyloid status (68 Aβ‐, 41 Aβ+). We used a standard “metaROI” composed of FreeSurfer (Desikan‐Killiany) ‐based ROIs in temporal, parietal and cingulate cortex to quantify R1 and FDG in all participants to compare R1 and FDG in the detection of between‐group differences with a one‐way ANOVA, and classification of participants with logistic regression models. Relationships between R1 or FDG and dementia severity, measured as the CDR sum of boxes, were examined in clinically impaired patients in multiple FreeSurfer‐based regions of interest.ResultR1 and FDG were both significantly lower in patients than in CN groups (R1: F(2,191) = 70.5, p<0.000001; FDG: F(2,191) = 87.9, p<0.000001), which did not differ significantly (Figure 1). FDG and R1 were both able to distinguish between patients and CN participants similarly, with sensitivity and specificity ranging from 80‐86% (Figure 2). R1 and FDG were associated with CDR sum of boxes in a similar set of frontal, temporal, and parietal regions, although FDG associations were stronger and more extensive (Figure 3).ConclusionR1 and FDG perform similarly in differentiating dementia patients and controls. Relationships between FDG/R1 and cognitive performance are similar, although FDG shows more extensive associations. R1 measures obtained from dynamic PIB‐PET scans are useful indicators of neurodegeneration which can substitute for FDG in many situations.
Differential effects of comorbid Lewy body and Alzheimer’s disease pathology on regional FDG‐PET patterns
Authors: Silva‐Rodríguez Jesús , Labrador‐Espinosa Miguel , Moscoso Alexis , Schöll Michael , Mir Pablo , Grothe Michel J. 
Published: December 2022

AbstractBackgroundIn differential dementia diagnosis, an FDG‐PET pattern of pronounced posterior‐occipital hypometabolism with relative sparing of the posterior cingulate cortex (PCC) and medial temporal lobe (MTL) is indicative of an underlying Lewy body (LB) vs Alzheimer’s disease (AD) pathology. However, LB and AD pathology are often comorbid, and in patients with LB dementia the presence of AD co‐pathology correlates with a more AD‐like neurodegeneration pattern. Here we studied how concomitant LB and AD pathology affects regional FDG‐PET patterns in patients with AD dementia.MethodThe study included 52 patients from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had a final diagnosis of AD dementia (N=46) or amnestic mild cognitive impairment (N=6) and had an ante‐mortem FDG‐PET scan available (FDG‐PET to death interval: 3.4±2.4 years). Twenty‐one patients had autopsy‐confirmed AD without comorbid LB (‘pure‐AD’), 24 had AD with LB co‐pathology (‘AD‐LB’), and 7 had LB with no or low evidence of AD pathology (‘pure‐LB’). Pathologic groups were compared on regional FDG‐PET SUVRs, the “cingulate island sign” ratio (CISr; PCC/(precuneus+cuneus) SUVR), as well as neuropathologic ratings of substantia nigra neuron loss (SNnl). A complementary analysis assessed continuous associations of AD co‐pathology (Braak tau stage) with regional FDG‐PET SUVR and the CISr in cases with LB pathology (pure‐LB+AD‐LB).ResultCompared to healthy controls (N=179), both pure‐AD and AD‐LB showed highly similar patterns of AD‐typical temporo‐parietal hypometabolism (Fig. 1), and neither regional FDG‐PET SUVRs, CISr, nor SNnl differed between the groups. By contrast, pure‐LB showed the expected pattern of pronounced occipital hypometabolism with relative sparing of the MTL, and CISr and SNnl were significantly higher compared to both pure‐AD and AD‐LB (p<0.05). Across cases with LB pathology, higher Braak tau stage was significantly correlated with a lower CISr (Spearman’s ρ=‐0.53, p=0.002), less occipital (ρ=‐0.37, p=0.043), and more MTL (ρ=0.36, p=0.047) hypometabolism.ConclusionIn autopsy‐confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG‐PET pattern, which may complicate in‐vivo detection of this comorbid condition. By contrast, we confirm and extend previous findings that AD co‐pathology associates with a more AD‐like neurodegeneration pattern in cases with LB pathology.