bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aging research in the time of COVID‐19: A telephone screen for subjective cognitive concerns in community‐dwelling ethnically diverse older adults
Authors: Nester Caroline O. , Mogle Jacqueline , Katz Mindy J. , Wang Cuiling , Lipton Richard B. , Derby Carol A. , Rabin Laura 
Published: December 2021

AbstractBackgroundThere is an urgent need for validation of remotely‐administered cognitive screens to identify older adults at risk for dementia, to monitor disease progression, and to facilitate follow‐up when in‐person visits are not feasible. Restrictions on in‐person cognitive assessments due to COVID‐19 have spurred a growing literature on telephone‐based cognitive screening. However, few studies have evaluated the value of telephone‐administered screens of subjective cognitive concerns (SCC), an important early marker of dementia‐risk.MethodEinstein Aging Study participants (subsample, n=455; Mage=77.0; Myears education=15.0; 64.1% women; 46.4% White) completed the Telephone Screen for Subjective Cognitive Concerns (T‐SSCC), a 16‐item measure of self‐reported memory, language, executive functioning, visuospatial/navigation, concentration, calculation, and mental clarity concerns, as well as the Telephone Montreal Cognitive Assessment (T‐MoCA). In‐person assessments included the paper‐and‐pencil Cognitive Change Index (CCI) and comprehensive neuropsychological evaluation. Classification as cognitively normal (CN; n=288) or mild cognitive impairment (MCI; n=153) was based on Jak/Bondi criteria. Primary analyses included correlations between the objective and subjective screening instruments, and logistic regression to evaluate the association between the T‐SSCC and MCI status.ResultTotal endorsement of concerns on the T‐SSCC (OR 1.095, CI 1.018‐1.178, p=0.015) was significantly associated with MCI status. In particular, endorsement of “Do any of these problems interfere with your daily life?” was strongly related to MCI (OR 2.296, CI 1.284‐4.108, p=0.005). The T‐SSCC was moderately correlated with the in‐person CCI (r[114]=0.577, p<0.001). A small but significant relationship was observed between the T‐SSCC and T‐MoCA (r[258]=‐0.206, p<0.001).ConclusionTo our knowledge, this is the first study to validate a telephone SCC screen in response to the crucial need for such remotely administered measures. The T‐SSCC was significantly associated MCI status; furthermore, specific items related to the impact of cognitive problems in daily life were particularly sensitive to MCI. Such SCC measures are brief, accessible, and well‐tolerated and may provide additionally valuable information that enhances remotely‐administered cognitive screens.
The technical reliability and stability of ATN quantification using the Fujirebio Lumipulse G1200 fully‐automated immunoassay instrument in cerebrospinal fluid
Authors: Celia Amanda M. , Ramirez Christopher E. , Trombetta Bianca A. , LaCasse Kathryn , Mattingly Zoe A. , Salloum Lauren , Orusakwe Amanze , Esquivel Rianne N. , Carlyle Becky C. , Kivisäkk Pia , Arnold Steven E. 
Published: December 2021

AbstractBackgroundFujirebio’s Lumipulse G1200 is designed to perform fully‐automated, rapid, random access immunoassays for biomarker quantification in biofluids. The Lumipulse instrument was used for quantification of the core Alzheimer’s Disease (AD) cerebrospinal fluid (CSF) biomarkers for Amyloid, Tau, and neurodegeneration (ATN): amyloid β 1–40 (Aβ40), amyloid β 1–42 (Aβ42), phosphorylated Tau 181 (pTau181), and total Tau (tTau). This study evaluated the reliability of the Lumipulse assays by measuring intra‐ and inter‐batch coefficients of variation (CV), and the correlation between Lumipulse values and the clinically used Athena ADmark Aβ42, pTau181 and tTau assays.Method423 CSF samples collected from diagnostic lumbar punctures between 2015 and 2020 were obtained from the MIND biorepository. Aβ40, Aβ42, tTau, and pTau were measured using the Lumipulse G1200 instrument in batches of 50‐60 samples. We tested 60 samples in duplicate to compare the intrabatch stability using the CVs between each pair. Each batch was run with a new set of calibrator controls at the start of each assay to ensure stability for each biomarker run. Finally, we correlated values from the Lumipulse with results from the clinical evaluation using the Athena ADmark test.ResultWe observed low variability in calibrator and control signals between batches with an overall calibrator signal CV of <5% for Aβ40 and tTau, and <10% for Aβ42 and pTau. Control signal CV values for all analytes were <5%. The mean duplicate CV across all batches was similarly stable at <10% for Aβ40, Aβ42, and tTau, and <5% for pTau. Subjects with CV >20% were seen <5% of the time. The correlations between Lumipulse and clinical ADmark results were high for pTau and tTau (R2>0.8 for both analytes), but lower for Aβ42 (R2∼0.5).ConclusionOur results demonstrated that the Lumipulse G1200 is a reliable, easy to use platform for ATN quantification with low sample to sample variability, and generally high correlation to established clinical standards. Inconsistent preanalytical sample handling of clinical send‐outs for Athena ADmark Aβ42 likely resulted in a poor correlation with Lumipulse G1200. The performance of the calibrators and controls proved that the standardization in each batch was consistent.
Diagnostic accuracy of the monocyte Aβ mid‐domain assay for CSF determined brain amyloid deposition
Authors: Kirsebom Bjørn Eivind , Wettergreen Marianne , Gisladottir Berglind , Sharma Kulbhushan , Christensen Erik , Fladby Tormod 
Published: December 2021

AbstractBackground Cells in the innate immune monocyte‐phagocyte system (MPS), including microglia and monocytes/macrophages are important players in Aβ clearance. MPS‐linked genetic variants are risk factors for Alzheimer’s disease, putatively linked to roles in Aβ clearance. The mid‐domain AβX‐34 peptide has recently been suggested as a marker of amyloid clearance. We hypothesize that the mid‐domain AβX‐34 peptides in peripheral blood‐derived monocytes reflect Aβ clearance efficiency and may serve as a biomarker of innate immune brain amyloid deposition. Here, we assess the diagnostic accuracy of blood monocyte derived AβX‐34 levels against an 18F flutemetamol amyloid PET determined CSF Aβ40/42 ratio cut‐off.Method First, to determine the optimum cut‐off for mesoscale discovery (MSD) CSF Aβ42/40 ratio, n=83 cases and controls from the dementia disease initiation (DDI) cohort with 18F flutemetamol amyloid PET scans were included. Using receiver operating curve (ROC) analysis we determined the optimum cut‐off value for the MSD CSF 42/40 ratio based on visual read of the PET images by a trained radiologist as the standard of truth. Next, AβX‐34 levels were determined using an immunoassay developed on the Quanterix Single Molecule Array (Simoa) platform using a proprietary anti‐mid‐domain sheep monoclonal antibody as capture. The detector is an anticomplex antibody using Bio‐Rad HuCAL technology ensuring optimal Aβ mid‐domain peptide specificity and assay sensitivity (Fladby US patent:9,625,474). Lastly, we included n=33 cases and controls and evaluated the diagnostic accuracy of monocyte derived AβX‐34 levels against the PET determined CSF Aβ40/42 ratio cut‐off using a ROC analysis.Result The MSD Aβ 42/40 ratio obtained an expected high diagnostic accuracy (AUC=.957) against amyloid PET. The monocyte derived AβX‐34 showed a comparatively lower, albeit adequate diagnostic accuracy (AUC=.808) against the Aβ 42/40 ratio cut‐off (see table 1 for details).Conclusion A new immunoassay quantitating Aβ mid‐domain peptides is a new innovative strategy integrating the innate immune system in the diagnostic armamentarium for AD. The monocyte derived mid‐domain AβX‐34 shows promise as a viable blood‐based biomarker of brain amyloid deposition. However, assessment of diagnostic accuracy in larger samples are warranted.
Early‐onset APOE‐ε4 carriers show greater decline in memory, language and executive function than late‐onset carriers
Authors: Logan Paige E. , Lane Kathleen A. , Manchella Mohit K. , Sanjay Apoorva Bharthur , Gao Sujuan , Apostolova Liana G. 
Published: December 2021

AbstractBackgroundApolipoprotein‐ε4 (APOE‐ε4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). However, whether APOE‐ε4 accelerates cognitive decline in AD has not been firmly established. We studied the rate of cognitive decline among early‐ (EOAD) and late‐onset (LOAD) APOE‐ε4 carriers vs non‐carriers on measures of memory, attention, language, and executive function.MethodEOAD and LOAD (onset‐age < or ≥65) subjects were selected from the National Alzheimer’s Coordinating Center (NACC) database. Mixed‐effects models were run separately for EOAD and LOAD with longitudinal neuropsychological measures as dependent variables. APOE‐ε4 carrier status, follow‐up time, and an APOE*time interaction were included as independent variables adjusting for age, sex, education, and disease severity (CDR‐SB) at baseline. For measures where ε4‐carriers had significantly more decline in both groups, mixed‐effects models in the combined samples were used with a three‐way interaction among APOE status, follow‐up time and onset‐age variables to determine whether APOE‐ε4 associated decline was similar between EOAD and LOAD.ResultSubject demographics are shown in Table 1. The estimated differences in annual cognitive change between ε4‐carriers and non‐carriers are shown in Table 2. Both EOAD and LOAD APOE‐ε4 carriers showed significant decline in Craft Immediate (p=0.0065 and p=0.0134, respectively), semantic fluency (p=0.0001 and p<0.0001, respectively), and Trail‐Making B scores (p=0.0028 and 0.0206, respectively) than non‐ε4 carriers. Only EOAD APOE‐ε4 carriers showed significantly greater decline in Craft Delayed recall than non‐ε4 carriers (p=0.0189). Only LOAD APOE‐ε4 carriers showed significantly greater decline on MoCA (p<0.0001), MINT (p<0.0001), and Trail‐Making A (p<0.0001) than non‐carriers. The accelerated rate of decline in two of the three cognitive tests that showed faster decline in APOE‐ε4 carriers in both EOAD and LOAD was significantly greater in EOAD, while one was trending (Craft Immediate, p=0.0042; semantic fluency, p<0.0001; Trail‐Making B, p=0.0942).ConclusionThese results suggest that APOE‐ε4 is associated with accelerated rate of decline in both LOAD and EOAD; however, the magnitude of the rate of decline is more pronounced in EOAD. Investigation in other large research consortia such as LEADS and ADNI can further characterize the genetic influences of APOE‐ε4 and other genetic risk factors on AD.
The association between personality and longitudinal cognitive trajectories is independent of baseline brain variables
Authors: De Leon Fransia S , Mungas Dan M , Gavett Brandon E , Fletcher Evan M , Farias Sarah Tomaszewski 
Published: December 2021

AbstractBackgroundPrevious work has shown that select personality and other interpersonal characteristics influence late‐life cognitive outcomes. However, it is not well understood whether these associations are dissociable from the effects of late‐life brain integrity. The current study examines whether personality characteristics are associated with cross‐sectional and longitudinal cognitive variables in a diverse cohort of older adults and whether these associations are independent of brain integrity as measured by structural MRI.Method157 participants (mean age 73.1±6.3 years) from the UC Davis ADC longitudinal Diversity Cohort were evaluated using the Spanish and English Neuropsychological Assessment Scales (SENAS) to assess verbal episodic memory, semantic memory, executive function, and spatial ability. The Big 5 personality measures were used to assess openness, conscientiousness, agreeableness, neuroticism, and extraversion as well as positive affect, sadness, meaning in life, and self‐efficacy. Baseline brain (MRI) variables including total gray matter volume, hippocampus volume and total white matter hyperintensity volume were also measured (n = 131). A parallel process, multi‐level model of the four longitudinal cognitive outcomes yielded intercept and linear slope random effects for each outcome. Slope random effects were highly correlated and summarized by a global slope second order factor. Global slope and individual intercepts were regressed on personality variables, covariates (age, gender, education, race/ethnicity, and recruitment source), and baseline brain variables.ResultPositive affect (p=0.004) and openness to new experience (p=0.009) demonstrated positive associations with longitudinal change in cognition that were independent of baseline brain variables and covariates (Table 2). Other personality variables, including conscientiousness, extraversion, neuroticism, agreeableness, sadness, meaning in life, and self‐efficacy did not demonstrate significant associations with cognitive change. Lower neuroticism and higher conscientiousness were associated with higher spatial ability intercepts, and lower sadness was associated with a higher episodic memory intercept, independent of covariates and brain variables.ConclusionPositive affect and openness are significantly associated with longitudinal cognitive trajectories, independent of demographics and cross‐sectional brain variables, including total gray matter volume, hippocampal volume, and total white matter hyperintensity volume. Future research will help to delineate how individual differences in personality and behavior relate to late‐life brain and cognitive changes.
Brain activation during episodic scene encoding is associated with amyloid and tau levels in amyloid‐positive older adults
Authors: Risacher Shannon L. , Deardorff Rachael , West John D. , Vosmeier Aaron , Tallman Eileen F. , McDonald Brenna C. , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. 
Published: December 2021

AbstractBackgroundThe relationship between amyloid and tau deposition and episodic memory‐related brain activity is understudied. Our goal was to determine the association between brain activation on fMRI during encoding of complex scenes and amyloid and tau deposition on PET.Methods91 individuals from the Indiana Memory and Aging Study (36 cognitively normal (CN), 27 subjective cognitive decline (SCD), 28 mild cognitive impairment (MCI)) underwent amyloid ([18F]florbetapir or [18F]florbetaben) and [18F]flortaucipir PET, structural and functional MRI, and clinical and cognitive testing. The fMRI task was a scene encoding paradigm in which the participant is asked to try to remember a set of complex scenes relative to viewing a scrambled control image. Amyloid Centiloid (CL) and tau SUVR images were generated using standard methods. Amyloid positivity was defined as global cortical CL≥21. Areas activated during the task (“main effect” (ME)) across all participants were determined (Figure 1A). Mean BOLD signals from ME regions, the entorhinal cortex (EC), and the inferior parietal lobule (IPL) were extracted. Mean cortical amyloid CL and tau SUVR from the bilateral EC, IPL, and lateral temporal lobe (LTL) were also extracted. Tau and amyloid were non‐normally distributed, so Spearman correlation models were used to evaluate the relationship of scene encoding activation and PET. Age, diagnosis, and sex were evaluated as covariates but did not change the observed pattern of results.ResultsSignificant association between tau and scene encoding activation was observed (Figure 1B). When limited to amyloid‐positive individuals only (n=28), the observed associations were considerably stronger between scene encoding activation and both amyloid CL level and tau deposition (Figure 1C‐E). Similar results were observed when limiting to the CN and SCD groups.ConclusionAmyloid and tau deposition are associated with reduced brain activity during episodic memory encoding in older adults at risk for AD. These findings suggest that brain function is another important biomarker to consider in both the temporal sequencing of biomarkers (Jack et al. 2013) and the A/T/N framework. Future studies in larger samples are warranted. Reference: Jack et al. (2013) Lancet Neurology.
Further preclinical development of a clinically effective bio‐therapeutic against Porphyromonas gingivalis
Authors: Nara Peter Lloyd 
Published: December 2021

AbstractBackgroundThe ever increasing list of broad adverse medical conditions associated with Porphyromonas gingivalis (Pg) infection associated with the long term, oral, biofilm‐associated colonization in humans leading to a state of chronic systemic inflammation with multiple organ system diseases (atherosclerosis, cardiovascular, stroke, diabetes type 2/metabolic syndrome, cancer, Alzheimer, etc.), stands in stark contrast to a grossly lacking set of effective treatments and/or prophylactic interventions.MethodUsing multiple technologies in microbiology, protein chemistry, proteomics, molecular biology, nucleic acid and protein sequencing, immunochemistry, scanning electron microscopy, biologics development, mid and large scale up hybridoma monoclonal antibody production and human chimeric antibody development and enzymology, an updated status of a newly developed precision biological will be presented.ResultKB‐001 a murine IgG1 binds directly to a unique hetero‐multimer antigen involved in the bacterial cargo IX transporter secretion protein complex through a high affinity bi‐valent binding (kD 10‐8‐9). About 40‐60 antibody molecules bind to emerging OMVs per bacterial are observed. In addition isolated OMVs demonstrate binding to the outer and inner membranes. Mechanism of action studies demonstrate that the antibody interferes with the proteolytic processing of the larger parent protein required for subsequent endo‐peptidase activity and assembly. More specifically, the binding of antibody to this complex prevents the maturation of the gingipains/LPS endo‐protease/peptidase system‐needed for its absolute survival and the production of its secreted outer membranes vesicles (OMVs) responsible for the majority of its systemic multi‐systems pathology. In an earlier human clinical trial, following its topical oral administration in advanced Pg infected periodontal patients, long term (12 months) prevention of re‐colonization of P. gingivalis following standard dental therapy was observed. In addition, the paratope binding domain from this murine Mab was successfully grafted onto a human IgG1 framework thus creating a second generation human‐chimeric, bio‐therapeutic antibody.ConclusionThese data now demonstrate the two precision bio‐therapeutics could be valuable for treating and/or preventing P. gingivalis infection in humans.
Neuroinflammation and flortaucipir PET in non‐fluent/agrammatic variant of primary progressive aphasia and/or apraxia of speech
Authors: Pascual Belen , Funk Quentin , Bradbury Kathleen , Jennings Cassandra , Rockers Elijah , Nakawah Mohammad O , Yu Meixiang , Beers David , Faridar Alireza , Appel Stanley , Fujita Masahiro , Masdeu Joseph C 
Published: December 2021

AbstractBackgroundNeuroinflammation, a hallmark of frontotemporal dementia, has been sparsely studied in vivo. However, neuroinflammation is a potentially important therapeutic target and biomarkers of inflammation would be welcome. To determine the anatomical specificity of a putative biomarker for inflammation, translocator protein 18 kDa (TSPO) imaging, we used 11C‐PBR28 PET to measure TSPO levels in patients with the non‐fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and/or apraxia of speech (AOS).MethodsSixteen patients with nfvPPP/AOS underwent PET using 11C‐PBR28 and 18F‐flortaucipir. All patients were PET amyloid‐negative except two, with a non‐AD flortaucipir PET. Thirty healthy controls underwent PET imaging using 11C‐PBR28 (13 controls) or 18F‐flortaucipir (17 controls). Patients (9/16 women, mean age 65±5.9 years) did not differ significantly in age from the controls (17/30 women, mean age 66±9.3 years). V
T values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. All images were corrected for partial volume effect. A full factorial analysis was performed on V
T and SUVR values between patients and controls at the voxel‐wise level.ResultsCompared to controls, patients showed increased V
T and SUVR values (p < 0.001 uncorrected) in left inferior, middle and superior frontal gyri, as well as in the left putamen and pallidum. However, peak uptake of 18F‐flortaucipir was localized in Broca’s area, epicenter of the pathology, while the distribution of 11C‐PBR28 V
T was more extensive in the frontal lobe, including precentral gyrus, and other regions outside of the frontal lobe, as the supramarginal gyrus and superior temporal sulcus, as well as a small area in the posterior extent of the right inferior frontal gyrus.Conclusions
11C‐PBR28 and 18F‐flortaucipir uptake patterns corresponded to anatomical areas known to be related to the specific language functions that are impaired in nfvPPA and apraxia of speech. Thus, 11C‐PBR28 seems to be a suitable radioligand for detecting neuroinflammation in nfvPPA. Furthermore, the more extensive anatomical distribution of abnormal 11C‐PBR28 uptake, as compared to 18F‐flortaucipir uptake, suggests that inflammation is key to the progression of the pathologic process in nfvPPA.
Deep learning–based genome‐wide association analysis in Alzheimer’s disease
Authors: Jo Taeho , Nho Kwangsik , Saykin Andrew J. 
Published: December 2021

AbstractBackgroundGenome‐wide association study (GWAS) designs are widely used to identify genetic loci associated with Alzheimer’s disease (AD) by performing a statistical test for each single‐nucleotide polymorphism (SNP). This creates a significant multiple testing challenge. Deep learning has demonstrated remarkable ability to identify non‐linear patterns using large data sets but application to AD genetics has been limited. Here we report preliminary results of a deep learning framework developed to identify AD‐associated genetic variation on a genome‐wide scale.MethodWe used genome‐wide genotyping data (12,448,786 SNPs following imputation) from 916 participants in the Alzheimer’s Disease Neuroimaging Initiative (458 cognitively normal controls and 458 AD patients). A convolutional neural network (CNN) consisting of convolutional, pooling and fully connected Softmax layers was used in a two‐stage approach. Data was divided into training‐testing‐validation sets (60:20:20 ratio). Area under the curve (AUC) was used to assess the model performance.ResultThe first stage of the deep learning approach identified 2,335 candidate genetic regions (93,400 SNPs) as associated with AD. The second stage investigated the association of identified SNPs with AD by calculating p‐values for each SNP based on AD influence z‐scores derived from the deep learning model. This approach identified genetic loci in the APOE region as most highly associated with AD (p‐value < 5X10‐8). Case/control classification using the identified SNPs yielded mean AUCs of 0.74, 0.79, 0.82, 0.90 for the thresholds of p‐value = 1x10‐5 (114 SNPs), 1x10‐4 (243 SNPs), 1x10‐3 (724 SNPs) and 1x10‐2 (2,846 SNPs), respectively (Fig. 1) and mean accuracies were 0.66, 0.69, 0.73, and 0.81, respectively.ConclusionPreliminary results indicate that a deep learning approach can be used to identify AD‐associated genetic loci and reduce the computational complexity to detect nonlinear interactions between SNPs, which may yield enhanced prediction accuracy for AD risk using genetic information. Future refinements of the deep learning framework are planned, including methods to reduce computational time and integrate additional omics layers and clinical data, as well as validation with independent replication samples.