bluuebunny/crossref_metadata_2025_split huggingface dataset:
MRI markers of accelerated brain aging and misappraisal of sleep depth
Authors: Baril Andree‐Ann , Mysliwiec Vincent , Beiser Alexa S. , Redline Susan , DeCarli Charles S. , Seshadri Sudha , Pase Matthew P. , Himali Jayandra J. 
Published: December 2021

AbstractBackgroundSlow‐wave sleep (SWS) is the deepest sleep stage, and has been linked to many important physiological functions, including the cerebral metabolic clearance of toxins associated with Alzheimer’s disease. SWS loss might correlate with accelerated brain aging. However, older individuals and people with cognitive impairment have an impaired ability to appraise their sleep, suggesting that accelerated brain aging might affect how sleep depth is perceived. The purpose of this study was to evaluate whether misappraisal of sleep depth was associated with MRI markers of accelerated brain aging.MethodWe studied 242 participants (mean: 62.0±8.7 years) participants in the Framingham Heart Study Offspring Cohort that were evaluated with an overnight in‐home polysomnography and an MRI 3.4 years later on average. Self‐reported sleep depth (whether sleep was light or deep) on the night of the polysomnography was compared to objective SWS (percent of total sleep spent in SWS, separated by the median). Four groups were created: 36% of the sample had consistent appraisal of deep sleep; 12% of the sample had consistent appraisal of light sleep; 36% misappraised their light sleep as deep; and 16% misappraised their deep sleep as light. We evaluated total brain volume, cortical gray matter volume, and subcortical gray matter volume on MRI. A first set of models were adjusted for age, sex, time between MRI and neuropsychology; a second set of models were additionally adjusted for APOE4 allele status, body mass index, sleeping pills, depression, and stroke risk.ResultParticipants who misappraised light sleep, i.e., reported deep sleep but had lower SWS, had lower cortical gray matter volume (model 1: β±SE=‐0.62±0.26, p=0.018; model 2: ‐0.56±0.27, p=0.036) compared to those that reported deep sleep with higher SWS. We also observed a trend for lower subcortical gray matter volume in the same group (model 1:β±SE=‐0.09±0.05, p=0.084). No other between‐group differences were observed.ConclusionParticipants with lower SWS that reported their sleep as deep displayed lower cortical volume. Accelerated brain aging might affect the ability to appropriately perceived sleep depth, which could be occurring in preclinical stages of dementia. Relying on self‐report sleep depth may introduce systematic misclassification.
An increase in fatty acid indices in cerebrospinal fluid of mild cognitive impairment precedes a decrease in Alzheimer’s
Authors: Fonteh Alfred N. , Cipolla Matthew , Arakaki Xianghong , Chui Helena C. , Harrington Michael G. 
Published: December 2021

AbstractBackgroundProcessing of membrane‐bound amyloid precursor protein (APP) may produce toxic amyloidogenic or less toxic non‐amyloidogenic amyloid (Aβ) peptides. We propose that brain membrane lipid composition and metabolism can dictate APP processing.MethodUsing neuropsychology measures, brain MRI, and consensus clinical conferencing, we classify three groups of elderly subjects: cognitively healthy (CH, n=70), mild cognitive impairment (MCI, n=40), and Alzheimer’s disease (AD, n=25). We fractionated CSF and determined the fatty acid composition of the unesterified fatty acid (UFA), the supernatant fluid (SF), and the nanoparticulate (NP) fraction using gas chromatography coupled with negative ion/chemical ionization mass spectrometry. We determined fatty acid indices for each fraction for chain length, unsaturation, peroxidation, and desaturase.ResultChain length, unsaturation, peroxidation, and desaturase indices were significantly different in the CSF fractions (p<0.0001). UFA carbon‐chain length, unsaturation, and peroxidation indices were higher in CH and MCI than in AD. In contrast, these indices did not significantly differ in the other CSF fractions. The UFA desaturase index was significantly higher in MCI (0.32±0.14) than in CH (0.26±0.2, adjusted p‐value (q) = 0.0220)) and AD (0.16±0.11, q <0.0001). In the SF and NP fractions, the desaturase index was lower in AD than MCI and CH. The changes in fatty acid indices were not associated with age, sex, BMI, and ApoE genotype.ConclusionOur studies show the compartmentalization of fatty acid metabolism in CSF fractions and changes in the AD spectrum. A higher carbon chain length, unsaturation, peroxidation, and desaturase index in MCI suggest higher lipid membrane turnover. A lower desaturase, peroxidase, and desaturase index in AD suggests enhanced lipolysis and oxidation of lipids. These data suggest that lipolysis and oxidation are features of AD pathophysiology, and monitoring fatty acid indices can help effectively monitor new therapies.
Amyloid time: Quantifying the onset of abnormal biomarkers and cognitive impairment along the Alzheimer’s disease continuum
Authors: Betthauser Tobey J. , Koscik Rebecca L. , Jonaitis Erin M. , Van Hulle Carol A. , Basche Kristin E. , Kohli Akshay , Suridjan Ivonne , Kollmorgen Gwendlyn , Chin Nathaniel A. , Mueller Kimberly D. , Clark Lindsay R. , Christian Bradley T. , Okonkwo Ozioma C. , Bendlin Barbara B. , Asthana Sanjay , Carlsson Cynthia M. , Zetterberg Henrik , Blennow Kaj , Johnson Sterling C. 
Published: December 2021

AbstractBackgroundQuantifying the temporal progression of key pathophysiological events in Alzheimer’s disease is crucial for staging disease, dementia risk assessment, and informing clinical trials. This work extends a novel algorithm (sampled iterative local linear approximation; SILLA) developed for modeling PET trajectories to: 1) generate a unified CSF and PET amyloid accumulation timeline, and 2) characterize the temporal progression of biomarker and cognitive changes in AD.Method941 participants from the Wisconsin Registry of Alzheimer’s Prevention, Wisconsin Alzheimer’s Disease Research Center, and Statins in Healthy, At‐Risk Adults: Impact on Amyloid and Regional Perfusion studies underwent [C‐11]PiB PET and/or lumbar puncture; and a subset underwent [F‐18]MK‐6240 PET and anatomical MRI using standardized protocols (Table 1). Amyloid burden was quantified from cortical PiB DVR and CSF Aβ42/40. Amyloid Time, quantified as years from CSF Aβ42/40 positivity, was estimated by simultaneously modeling Aβ42/40 and PiB DVR using an extension of the SILLA method in a subset of 248 participants with both measurements. CSF biomarkers measured using the exploratory Roche NeuroToolKit assays, imaging biomarkers, and cognitive impairment (global CDR, CDR SOB, and diagnosis) were plotted as a function of Amyloid Time. Time between key AD events was estimated using LOWESS curves and positivity thresholds for each AD biomarker and CDR scores.ResultFigure 1 depicts biomarker thresholds. Amyloid Time suggested PET Aβ+, CSF T+, PET T+, CDR=0.5, and CDR=1 occurred 4.0, 12.0, 13.8, 17.7, and 22.0 years following Aβ42/40 positivity (Figure 2, Table 2). Heterogeneity was observed in tau levels relative to Amyloid Time for individual cases. Those with worsening CDR generally had high amyloid and at least one T+ biomarker.ConclusionAmyloid Time based on combined CSF and PET amyloid biomarkers and the SILLA algorithm provides a novel way to quantify the duration of amyloid exposure from the earliest pathophysiologic CSF changes to dementia onset in AD within individuals. This enables characterization of the time between key AD events, which could inform prognosis, identify intervention timing for novel therapies, and enable exploration of mechanisms related to resistance and/or resilience.
Sex and cerebral small vessel disease‐specific longitudinal trajectories of amyloid, tau, and neurodegeneration
Authors: Shaaban C. Elizabeth , Snitz Beth E , Tudorascu Dana L , Lopresti Brian J , Royse Sarah K , Yu Zheming , Aizenstein Howard J , Klunk William E , Cohen Ann D 
Published: December 2021

AbstractBackgroundThe AT(N) model of Alzheimer’s disease (AD) posits a temporal evolution of β‐amyloid (Aβ) accumulation followed by tau then neurodegeneration. We investigated whether longitudinal relationships of these pathologies varied by sex and cerebral small vessel disease burden (cSVD), hypothesizing stronger associations in women and those with high baseline cSVD.MethodParticipants included 37 non‐demented older adults (mean 74 y/o at inclusion; 59% female; 89% white; 29% APOE4+). Tau was measured once at time 0 using 18F‐AV‐1451 in an AD composite region of interest. Global amyloid and cerebral metabolism in lateral temporal lobe (neurodegeneration) were measured at repeated annual visits (8 years before tau‐PET to 2 years after), using 11C‐PiB and 18F‐fluorodeoxyglucose (FDG)‐PET. cSVD at study inclusion was characterized by high or low white matter hyperintensity (WMH) volume on MRI. We calculated individual slopes of Aβ and cerebral metabolism up to the tau‐PET visit (time ‐8 to 0) using linear mixed effects models. Using age‐adjusted linear regression models, we examined associations of Aβ slope, tau, and cerebral metabolism slope or metabolism at the final visit (time≥0). We tested effect modification by sex and WMH using interaction terms and stratified analyses when interaction p<0.10.ResultAssociations of Aβ slope with tau varied by sex (p‐interaction=0.007) but not WMH. Greater increase in Aβ slope was associated with greater tau in women (β=3.5, p=0.004), but not men (β= ‐1.2, p=0.34). Tau did not predict cerebral metabolism at the final FDG visit (β=0.10, p=0.67), but increasing Aβ slope predicted hypometabolism at the final FDG visit (β= ‐2.1, p=0.01). Neither of these relationships varied by sex or WMH. Associations of cerebral metabolism slope with tau varied by sex (p‐interaction=0.08), but not WMH. Decreasing cerebral metabolism slope was associated with greater tau in women (β= ‐16.3, p=0.05), but not men (β=4.7, p=0.59). Further adjustment for APOE4 (N=31) did not appreciably alter results.ConclusionIn non‐demented older adults, we found that associations of Aβ and cerebral hypometabolism with later increased tau were stronger in women than men; cSVD did not modify these associations. Tau did not predict later cerebral metabolism, while Aβ did.
Comparison of actuarial and conventional MCI criteria in a community‐based prospective cohort study: The Adult Changes in Thought (ACT) study
Authors: Eppig Joel S , Madan Raghav , Arrota Kayela , McCurry Susan M , Bowen James D , McCormick Wayne , Cholerton Brenna , Craft Suzanne , Crane Paul K. , Larson Eric B. , Trittschuh Emily H 
Published: December 2021

AbstractBackgroundOperationalizations of mild cognitive impairment (MCI) are inconsistent. Actuarial criteria have been proposed to improve accuracy. We investigated dementia and Alzheimer’s disease (AD) conversion for conventional versus actuarial MCI criteria in a community‐based prospective cohort study.Method1413 non‐demented participants were administered measures from memory, language, and attention/executive function domains. We used published norms to generate demographically‐adjusted z‐scores. Conventional MCI criteria were met for scores >1.5sd below the mean on any measure. Actuarial MCI criteria were met for 2 scores >1.0sd below the mean in one domain or a score >1.0sd below the mean in all three domains. Participants were followed biennially to capture dementia incidence. A consensus conference used DSM‐IV dementia criteria and NINDS‐ADRDA AD criteria for diagnosis. We focused on 6‐year outcomes following MCI categorization.ResultAt baseline, n=875 (62%) met neither conventional nor actuarial MCI criteria, n=16 (1%) met only actuarial MCI criteria, n=383 (27%) met only conventional MCI criteria, and n=139 (10%) met both. Demographic characteristics are in Table 1. Education differed across criteria (p<0.0001); more people with lower education met only conventional MCI criteria. During follow up (7090 person‐years, mean=5 years), there were 175 incident dementia cases, of whom 110 (63%) met conventional and 53 (30%) met actuarial MCI criteria at their baseline neuropsychological evaluation. In a Cox model adjusting for age, sex, education, and race/ethnicity, the conventional MCI dementia hazard ratio (HR) was 2.93 (95% CI 2.15, 4.01, p<0.001), and the actuarial MCI HR was 3.62 (95% CI 2.60, 5.03; p<0.001). There were 154 incident AD cases; 101 (66%) met conventional and 49 (32%) met actuarial criteria. The adjusted conventional MCI AD HR was 3.25 (95% CI 2.32, 4.56, p<0.001), and the actuarial MCI AD HR was 3.81 (95% CI 2.69, 5.38, p<0.001).ConclusionBoth conventional and actuarial MCI criteria identified individuals at higher risk of developing dementia and AD over 6 years of follow‐up. Conventional criteria flag a higher proportion of those who ultimately developed dementia and AD compared to actuarial criteria. However, hazard ratios for progression to dementia and AD were slightly higher for the actuarial criteria.
Regulation of intracellular innate immune amyloid beta (aβ) clearance
Authors: Wettergreen Marianne , Gisladottir Berglind , Kirsebom Bjørn Eivind , Christensen Erik , Sharma Kulbhushan , Fladby Tormod 
Published: December 2021

AbstractBackgroundInnate immune Aβ clearance may be involved in Alzheimer’s disease (AD) etiology and treatment response following anti‐amyloid immunotherapy. Regulation of intracellular Aβ clearance is not measured in AD risk‐ or diagnostic assessments, and pathways and mechanisms are insufficiently mapped. We present assays for Aβ catalysis in myeloid cells (THP‐1 cells and human iPSC microglia).MethodTHP‐1 cells were differentiated toward macrophages, and treated with various inhibitors including IDE inhibitor (6bK, Tocris),BACE1 inhibitor (LY2886721, Tocris), Nep inhibitor (Phosphoramidon, Tocris), Bafilomycin A1(Sigma)(1h) and Rapamycin (Sigma) (18h) before adding 100 ng/ml Aβ40 (2h), followed by 4h chase. For AD patient derived microglia, reprogrammed iPSCs were differentiated through a myeloid progenitor stage. Mature microglia were characterized by qPCR, Immunofluorescence and phagocytosis assay. Two immunoassays were developed on the Simoa platform using proprietary sheep monoclonal antibodies (Pre Diagnostics, Norway). Both assays employ an Aβ c‐terminal antibody for capture (AB.4D7). Assay 20‐x employs a specific Aβ20’ cut point antibody (NH2‐20.2B8) and assay x‐40 a linear mid‐domain antibody (AB.2A9) binding full length Aβ as detector.Result1) Innate immune cells (THP1, microglia) catabolize Aβ 1‐40 producing 20‐x fragments. 2) Inhibition of Nep and BACE1 reduces the production of 20‐x fragment of Aβ in THP1 cells. 3) Autophagy inhibitor BafA1 increases both 1‐40 and 20‐x fragments indicating the role of the endo‐lysosomal system in the degradation of full length and 20‐x Aβ. 4) Autophagy inducer, Rapamycin reduces both 1‐40 and 20‐x fragments indicating the role of mTOR mediated autophagy and the endo‐lysosomal system in the degradation of full length and 20‐x Aβ.Conclusion1) We demonstrate a novel assay for Aβ degradation by Innate immune cells including THP‐1 and iPSC derived microglia. 2) Inhibition of Nep and BACE1 reduces 20‐x peptide generation indicating this as a potential marker for Aβ. 3) Modulation of autophagy affects 20‐x peptide generation indicating the potential of targeting endo‐lysosomal and autophagic pathway against AD.
Utility of combined plasma amyloid beta 40, amyloid beta 42, total tau, and NfL along with a measure of cognitive functioning in detecting cognitive impairment among Hispanic, Mexican Americans compared to non‐Hispanic whites
Authors: Petersen Melissa , Hall James R. , Zhang Fan E. , Mozdbar Sima , Johnson Leigh Ann , Yaffe Kristine , Braskie Meredith N. , King Kevin , Toga Arthur W. , O'Bryant Sid ,   Health and Aging Brain Study (HABS‐HD) Team
Published: December 2021

AbstractBackgroundThe AT(N) diagnostic framework for Alzheimer’s Disease (AD) highlights the importance of specific plasma biomarkers associated with neurodegeneration (Amyloid Beta, Tau) and neuronal injury (Neurofilament light chain [Nf‐L]). Despite a wealth of research on such plasma biomarkers of AD pathology, limited work has specifically been conducted among minority populations. Our study sought to examine a combination of AD biomarkers both alone and in combination with a select measure of cognition among Hispanic, Mexican Americans (MA) and Non‐Hispanics Whites (NHW) in detecting cognitive impairment.MethodPlasma samples were assayed on n=1703 participants (n= 890 MA [n=676 Normal Cognition [NC]; n=214 Cognitively Impaired [CI]]; n= 813 NHW [n=673 NC; n=140 CI]) enrolled in a study of health disparities. Plasma Amyloid Beta 40, Amyloid Beta 42, Total Tau, and Nf‐L were assayed using Simoa. A measure of verbal fluency (FAS) was utilized. The samples were randomly split (70/30) to allow for a training and test set. Random Forest (RF) models were conducted with performance on the test set reported.ResultAmong MA, AD biomarkers alone produced an area under the curve (AUC) of 0.50 with a sensitivity (SN) of 0.77 and specificity (SP) of 0.17. When the AD biomarkers were included along with a measure of verbal fluency (FAS)(biomarker‐cognitive profile), AUC increased to 0.63 with an SN of 0.82 and SP of 0.17. Inclusion of demographics (age, gender, education) to the biomarker‐cognitive profile increased only SP, which reached 0.50. Among NHW, AD biomarkers alone produced an AUC of 0.35 with SN of 0.88 and SP of 0.74. The combined biomarker‐cognitive profile increased AUC to 0.66 with an SN of 0.42 and SP of 0.81. The addition of demographics further increased AUC to 0.72 (SN=0.53; SP=0.88).ConclusionDetection accuracy differed by ethnicity with a broader range shown among NHW (AUCs 0.35‐0.72) compared to MA (AUCs 0.50‐0.63). Utility of AD plasma biomarkers improved with the addition of a select cognitive measure. This is consistent with prior work showing the application of a combined model (biomarker‐cognitive profile) to distinguish those with cognitive impairment. The addition of demographic factors improved the detection only for NHW.
A new blood‐based biomarker of Aβ clearance: The monocyte Aβ mid‐domain assay
Authors: Christensen Erik , Wettergreen Marianne , Torsetnes Silje Bøen , Gisladottir Berglind , Fladby Tormod 
Published: December 2021

AbstractBackgroundDeficiency in cerebral Amyloid beta (Aβ) clearance is implicated in the pathogenesis of Alzheimer’s disease (AD), and Aβ clearance systems are potential therapeutic targets in AD. Clearance of Aβ is a complex process were phagocytosis and degradation of Aβ are two important components. Innate immune‐linked genetic risk factors contribute to AD, and innate immune cells; microglia in the brain and monocytes/macrophages in the peripheral blood (PB), phagocytose Aβ and contribute to clearance. Our objective was to develop an assay measuring Aβ mid‐domain peptides in relevant biological specimens. The intracellular concentration of peptides containing mid‐domain fragments may reflect phagocytic activity or Aβ degradation efficiency.MethodAn immunoassay on the Quanterix Single Molecule Array (Simoa) platform was developed against an Ab 20‐34 peptide using a proprietary anti‐mid‐domain sheep monoclonal antibody as capture antibody (2A9). The detector reagent consists of an anticomplex antibody using Bio‐Rad HuCAL technology (H3) ensuring the optimal Aβ mid‐domain peptide specificity and assay sensitivity. Monocytes were isolated from 8 ml blood samples using a combination of BD CPT blood sampling tubes and RosetteSep antibodies from StemCell.ResultThe 2A9/H3 immunoassay run on the Simoa platform detected Aβ mid‐domain containing peptides with a lower limit of quantification (LLOQ) of approximately 0,7 pg/ml resulting in measurable levels of the peptides in both CSF and monocyte lysates (figure 1 a).ConclusionAs shown in figure 1 b, the 2A9/H3 combination has a high specificity for mid‐domain restricted peptides. Here we show that as used in a sensitive Simoa‐assay, this assay detects Aβ mid‐domain containing peptides both in CSF and monocyte lysates, and may serve as a tool for PB measurement of Aβ catabolism in both disease progression studies and intervention studies. The PreADx ™ assay is an accurate and highly sensitive immunoassay for quantification of mid domain Aβ peptides in relevant biological fluids and cells. The assay demonstrates high precision with monocyte lysates and linearity in spiking and dilution experiments (not shown).
The effect of attending schools with higher ability peers on memory and language abilities in later‐life
Authors: Seblova Dominika , Dworkin Jordan J , Peters Kelly , Lapham Susan , Prescott Carol Arlene , Glymour Maria M , Manly Jennifer J 
Published: December 2021

AbstractBackgroundPeers influence adolescent behavior, educational, and health outcomes. Evaluating the influence of school‐mates’ cognitive aptitude on later‐life cognition is important for understanding the role of school segregation and tracking in establishing inequality. Yet, few studies have the data to study this. We used a national high‐school based study followed up 58 years later to examine if attending schools with more skilled peers predicts individual later‐life cognition.MethodIn 1960, about 5% of US high schools participated in Project Talent (n=377,000), where students reported demographics and completed aptitude tests. Some of these students were enrolled in 2018/2019 (mean age=74.6) in the Project Talent Aging Study (PTAS). For each PTAS participant, we calculated peer cognitive aptitude as the average of cognitive aptitudes of all other students who were in the same high school. The outcome, later‐life cognition, was operationalized as z‐score composites for language (semantic and phonemic fluency) and memory (CERAD learning list and delayed recall). For each outcome we estimated multilevel linear models to account for school clustering. All models were adjusted for age, sex/gender, parental education; secondary models were also adjusted for the participant’s own adolescent cognitive aptitude. To examine heterogeneity of the association, we evaluated interactions of peer ability with sex/gender, and the participant’s own adolescent cognitive aptitude.ResultParticipants were predominantly non‐Hispanic White (80.4%) and women (52.6%). Attending schools with peers who averaged 1 standard deviation higher on cognitive aptitude predicted better later‐life cognition prior to adjustment for own aptitude (language: β=0.162, 95% CI: 0.120, 0.205; memory: β=0.084, 95% CI: 0.041, 0.126), but not after adjustment. However, for women (β=0.045, 95% CI: ‐0.012, 0.101) and those with below mean adolescent cognitive aptitude (β=0.091; 95% CI: 0.016, 0.166), attending schools with higher ability peers predicted better later‐life language scores even after own ability was considered. There was no moderation of these relationships by race/ethnicity.ConclusionPeople with below average cognitive aptitude in adolescence had better language function 58 years later if they attended high schools with high aptitude peers. Future work will examine the plausible life‐course mechanisms to address why certain groups benefit more from schooling contextual factors.