bluuebunny/crossref_metadata_2025_split huggingface dataset:
A sensor technology to continuously monitor changes in cognition
Authors: Bowen Mary Elizabeth 
Published: December 2020

AbstractBackgroundResearchers are increasingly utilizing real‐time sensors with ultra‐wideband radio frequency identification device (UWB RFID) technology to continuously, automatically and unobtrusively track the behavior and movement of older adults across care settings (Bowen, Kearns, Crenshaw, & Stanhope, 2019; Bowen & Rowe, 2019; Bowen & Rowe, 2016). These systems can be integrated into the health care environment and are ecologically valid measures taken concurrently as adults perform everyday activities of daily living (ADL). The purpose of this study is to examine the use of a UWB RFID system for the early recognition of behaviors associated with cognitive decline among skilled nursing residents (N=23) of two health care facilities.MethodResidents were assessed continuously for an average of 10 months (SD=32.16 weeks). Scoring algorithms from the UWB RFID system utilized 1663 data points developed from x, y coordinates to measure the number and distance (meters) of continuous walking activity in a path. A path is defined as at least 60 seconds of walking and ends with a 30‐second stop. Cognitive function was measured by the Montreal Cognitive Assessment (Nasreddine, et al., 2005) and the Physical and Cognitive Performance Test (Bowen, Rowe, Ersek, Ibrahim, & Shea, 2017).ResultOn average, residents walked 1522.8 meters/week (SD=1572.7) with an average of 23.2 paths/week (SD=25.6). In multilevel models, accounting for ADL ability, an increased average number of paths per week was associated with decreased cognitive functioning (β= ‐0.65; p≤0.01).ConclusionContinuous walking in a path may be an early indicator of cognitive decline. Using an UWB RFID system may aid in the early detection and recognition of cognitive changes in this patient population. Importantly, these changes are also associated with other health events (e.g., falls, delirium, urinary tract infection, hospitalization) that may be ameliorable to intervention.
The role of the gut microbiome in cognitive function and Alzheimer’s disease
Authors: Bonnechère Bruno , Karamujić‐Čomić Hata , Radjabzadeh Djawad , Ahmad Shahzad , Ikram M. Arfan , Hankemeier Thomas , Kaddurah‐Daouk Rima F. , Uitterlinden André G. , Amin Najaf , Kraaij Robert , van Duijn Cornelia M. 
Published: December 2020

AbstractBackgroundAlthough the level of evidence suggesting a role of the gut microbiome in the pathogenesis of Alzheimer’s disease (AD) in human and animal models, the evidence in humans is currently based on small studies and cannot determine whether the gut microbiome has changed in AD patients as a cause of consequence of disease. To exclude reverse causation, we have studied the association of the gut microbiome to cognition in 1,184 healthy participants of the Rotterdam Study.MethodFecal microbiome of 1,184 participants from the Rotterdam Study was characterized by 16S rRNA profiling. Cognitive function was assessed using g‐factor. Linear regression was used to associate the gut microbiome to cognitive function adjusting for age, sex, time in mail, storage time, and use of proton pump inhibitors. Further, we performed a systematic literature review to assess the consistency of findings on the association of the gut microbiome in AD and mice. Finally, we assessed the relationship between these microbiota and the general cognitive function.ResultWe found that the relative abundance of the phylum Firmicutes in the gut is associated with a better cognition. The relative abundance of families Lachnospiraceae, Christensenellaceae, Rumininococcaceae and Clostridiaceae explain this association. The relative abundance of Klebsiella, a member of the Enterobacteriaceae family is associated with lower levels of cognition. These findings were independent of potential confounders such as age, BMI, alcohol, and use of medication. Of the 10 associations that we found, 9 could be replicated in the smaller case‐control studies conducted to date in AD.ConclusionThe present study finds that the relative abundance of the phylum Firmicutes in the gut is associated with a better cognition and the relative abundance of Klebsiella with lower levels of cognition. Taken together with studies published previously about AD, we find a relative reduction in phylum Firmicutes and an increased in Klebsiella is associated with lower cognition and dementia.
Entrainment of gamma oscillations by auditory chirp stimulation in Alzheimer’s disease patients
Authors: Sedghizadeh Mohammad Javad , Hasani Hosein , Lahijanian Mojtaba , Aghajan Hamid , Vahabi Zahra 
Published: December 2020

AbstractBackgroundHigh‐level cognitive processes such as binding the processed data from sensory modules with elements stored in the memory involve the activity of long‐range pyramidal cells. These excitatory neuronal populations also provide input to a population of GABAAergic inhibitory interneurons, which in turn recruit feedback links to suppress the activity of the pyramidal cells. Interneuron networks generate rhythmic synchronization in the Gamma band driven by the time constant of the GABA receptors. Disrupted or desynchronized Gamma oscillations have been observed in patients of Alzheimer’s disease (AD). Earlier works have proposed the deficit in coherence between oscillations measured by EEG electrodes across the frontal lobe in the Gamma band in response to olfactory stimulation as a diagnostic marker of AD. This study examines the strength and spatial spread of Gamma band activity induced by auditory chirp stimulation as a marker for AD. The chirp signal is designed to entrain a target frequency of 40Hz at which the populations of inhibitory interneurons are known to operate.MethodA session comprising 11 interleaved periods of 40sec ON and 20sec OFF auditory stimuli of 5kHz tone modulated by a 40Hz chirp at 0.1 duty cycle was administered to mild AD patients and non‐AD elderly participants with memory complaints, and EEG data were collected by a 10/20 system. Magnitude of 40Hz oscillations at different scalp positions during the ON cycles was measured as an indicator of the entrained Gamma oscillations.ResultWhile 40Hz oscillations were recorded across a majority of electrodes in non‐AD demented participants with particular strengths in the temporal and frontal areas, the 40Hz entrainment occurred for a limited number of electrodes in AD patients.ConclusionAuditory chirp stimulation at 40Hz results in spatially distinguishable patterns of entrained Gamma oscillations in AD patients and non‐AD demented participants, and hence suggests a marker for AD. Despite this difference, the fact that 40Hz entrainment still occurs in regions of the brain in AD patients offers a positive indication for the possibility to employ such stimulation to reinvigorate the operation of the involved neural circuitry in therapy campaigns. Further studies are needed to assess such possibility.
Effects of a WIN 55,212‐2‐based therapy in two mouse models of Alzheimer's disease
Authors: Schmitt Franziska , Bayer Thomas A , Ott Frederik W , Bouter Yvonne 
Published: December 2020

AbstractBackgroundLimited therapeutic effects of current Alzheimer treatments highlight the need for new research approaches. Targeting the endocannabinoid system could be such an approach. The endocannabinoid system plays a role in brain development, memory formation, and presynaptic activity as well as in neuro‐inflammatory processes and neuroprotection (Mechoulam et al., 2014; Salzet et al., 2000). Several in vitro studies showed that cannabinoids could stimulate phagocytosis and degradation of Aβ as well as stimulate the removal of intraneuronal Aβ in vitro (Currais et al., 2016). The current study aims to investigate the therapeutic potential of a WIN‐based Alzheimer’s disease therapy using mouse models of sporadic (Tg4‐42; Bouter et al., 2013) and familial (5xFAD; Oakley et al., 2006) Alzheimer’s disease. WIN 55,212‐2 (WIN) is a synthetic cannabinoid binding more efficiently to CB1 and CB2 receptors than Tetrahydrocannabinol.MethodTg4‐42 and 5XFAD mice were treated by intraperitoneal injections with the synthetic cannabinoid WIN 55,212‐2 (0,2mg/kg) over a period of 42 days. Sex‐ and age‐matched control groups are treated with vehicle solution (5% ethanol, 5% Tween80 in 0,9% sodium chloride solution). Spatial reference memory was assessed using the Morris water maze, motor performance with the Rotarod and anxiety behavior was evaluated using the elevated plus‐maze and the dark‐light box. 5xFAD mice carry five mutations strongly linked to amyloid processing. The effects of WIN on the Aβ pathology in 5XFAD mice will be investigated using immunohistochemistry and presented.ResultWIN 55,212‐22 treatment of Tg4‐42 mice showed increased spatial reference memory and increased motor performance in comparison to the control group. Preliminary data analysis of 5xFAD mice shows significant results pointing in the same direction. Analysis of 5xFAD mice will be completed and presented.ConclusionOur findings reinforce a cannabinoid‐based therapy as a promising strategy for treating Alzheimer’s disease with WIN 55,212‐22 as a possible candidate.
Platelet APP‐ratio correlates with CSF levels of Aβ1‐42 in Alzheimer’s disease patients
Authors: Sarno Tamires Alves , Talib Leda Leme , Joaquim Helena Passarelli Giroud , Radanovic Marcia , de França Bram Jessyka Maria , Gattaz Wagner Farid , Forlenza Orestes Vicente 
Published: December 2020

AbstractBackgroundThe cerebrospinal fluid (CSF) is reputed as the best humoral matrix to address Alzheimer´s disease (AD) biomarkers. AD‐related CSF biomarkers are largely related to intracerebral amyloidosis, and have proved useful for diagnostic purposes and prediction of dementia in high‐risk populations. Lower CSF concentrations of Aβ1‐42 have been consistently reported in AD. However, results with peripheral biomarkers have so far yielded less consistent results. Platelets are the main peripheral source of amyloid precursor protein (APP) and contain the enzymatic machinery required for its proteolytic metabolism. Previous studies have shown that platelet APP ratio (130/110 kDa sAPP) is reduced in AD.MethodWe enrolled 66 older adults (26 with AD and 40 cognitively unimpaired subjects). The expression of 110‐ and 130kDA secreted APP peptides (sAPP) was determined in platelets by Western blotting using 22C11 monoclonal antibody, to determine APP ratio (rAPP). CSF concentrations of Aβ1‐42 were determined by a multiplexed method using commercial kits (Innobia AlzBio3).ResultThere were no statistically significant differences in age (p=0.67) or gender distribution (χ2=0.155; p=0.69) across groups. Compared to controls, AD patients had lower mean platelet rAPP (AD: 1.26, SD0.5; controls: 2.07, SD0.93; p<0.001) and CSF Aβ1‐42 concentrations (AD: 319.04, SD146.7; controls: 450.84, SD 109.9; p=0.001). We also found positive correlations between platelet rAPP and CSF Aβ1‐42 (Spearman’s Rho=0.40; p=0.01).ConclusionOur findings confirm that platelet rAPP and CSF Aβ1‐42 are reduced in AD. We further show that these two parameters are correlated, indicating that platelet rAPP may be regarded as a surrogate marker of intracerebral accumulation of amyloid‐beta.
Socioeconomic status mediates racial differences seen using the AT(N) framework
Authors: Wisch Julie , Hudson Darrell , Coble Dean W. , Xiong Chengjie , Babulal Ganesh M. , Gordon Brian A. , Flores Shaney E. , Dincer Aylin , Benzinger Tammie L.S. , Morris John C. , Ances Beau M. , Meeker Karin L. 
Published: December 2020

AbstractBackgroundPrevious research suggests that African Americans are potentially at greater risk for developing Alzheimer disease (AD). Genetic, social, environmental, and cardiovascular factors may increase the risk of AD. The objectives of this project are as follows: (1) Assess neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences. (2) Consider mediating effects of socioeconomic status (SES) and cardiovascular risk factors on observed race differences.MethodsImaging measures of AT(N) (amyloid and tau positron emission tomography (PET) structural magnetic resonance imaging, and resting state functional connectivity (rs‐fc)) were collected from African American (n=169) and Caucasian (n=935) participants. Cardiovascular (white matter hyperintensities on MRI, blood pressure, and body mass index) and area‐based socioeconomic status (SES) were assessed as possible mediating factors in a multiple mediation analysis. This analysis assumed nonlinear relationships between the mediation effects and allowed for all four mediators to be considered simultaneously.ResultsCompared to Caucasian participants, African American participants had lower amyloid PET burden but greater neurodegeneration, as measured by decreased cortical volumes and decreased AD global rs‐fc signature. African American participants were substantially more likely to be female (64%) compared to Caucasian participants (55% female). Female participants had greater tau burden and decreased AD cortical signature volume; but no significant race by sex interactions were observed. African Americans had lower area‐based SES and higher blood pressure, BMI, and white matter hyperintensity volumes. These proposed mediators significantly influenced associations between race and cortical amyloid PET accumulation, AD cortical signature volume, and AD global rs‐fc signature. Area‐level SES in particular was a significant mediating factor, and BMI had a significant effect on amyloid burden.ConclusionObserved racial differences in AD are not primarily due to immutable, genetic differences, but rather modifiable factors fueled by differences in social contexts and resources, particularly area‐level SES. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies.
MK‐6240 imaging features, cognitive associations in preclinical Alzheimer’s disease and a case with imaging‐to‐postmortem correlates
Authors: Betthauser Tobey J. , Koscik Rebecca L. , Jonaitis Erin M. , Cody Karly Alex , Erickson Claire M , Mueller Kimberly D. , Clark Lindsay R. , Stone Charles K , Christian Bradley T. , Asthana Sanjay , Salamat Shahriar , Johnson Sterling C. 
Published: December 2020

AbstractBackgroundUnderstanding imaging features and detection limits of tau PET tracers is crucial for making accurate inference about underlying tau pathology, including critical implications for clinical treatment and prevention trials. This study investigates imaging features of the tau PET tracer MK‐6240 and associations with preclinical cognitive decline and beta‐amyloid with an emphasis on elucidating the earliest detectable MK‐6240 signal. These findings are contextualized with the first report of imaging‐to‐postmortem correlates for MK‐6240.MethodsParticipants recruited from the Wisconsin Registry for Alzheimer’s Prevention underwent longitudinal cognitive assessment, and PiB and MK‐6240 PET imaging. Three regional MK‐6240 composites were generated based on MK‐6240 spatial correlations (MTL, cortical, visual cortex). Linear mixed‐effects models probed relationships between longitudinal cognitive trajectories (three‐test Preclinical Alzheimer’s Cognitive Composite; PACC‐3), amyloid chronicity (estimated duration PiB(+) at baseline PACC‐3), and MK‐6240 in each composite region. MK‐6240 imaging outcomes were compared to neuropathological assessment for a 63 year‐old from the Wisconsin ADRC clinically diagnosed with early onset AD with PiB and MK‐6240 scans ∼2 months antemortem.ResultsInter‐regional MK‐6240 correlations indicated minimal spill‐in from extra‐axial signal for most brain regions with the lowest correlations observed in the MTL. Mixed‐effects models indicated a significant three‐way interaction between age, baseline amyloid chronicity and MK‐6240 SUVR on longitudinal PACC‐3 in all three composite regions. The three‐way interaction remained significant only in the MTL when excluding participants with Z(MK‐6240)>2 in the cortex or visual composite regions. Neuropathological assessment of the case with antemortem imaging indicated Thal phase 4 and Braak stage IV or V with grade 1 CAA. Asymmetry in the MTL and focal elevations were observed in MK‐6240 images in this case, but SUVR values were below regional cutoffs for tau positivity.ConclusionsSimilar to reports with other tau tracers, MK‐6240 imaging‐to‐postmortem correlates suggest that tau‐related PET signal may not be detectable until later neuropathological NFT stages. The neuropathology results combined with the cognitive findings suggest that MK‐6240 signal in the MTL is indicative of more extensive tau pathology than can be observed with PET and thereby is disease‐related. Further work is underway characterizing the spatial correspondence between MK‐6240 and tau pathology.
Inter‐cohort staging efficacy of gaussian process progression model for Alzheimer’s disease
Authors: Archetti Damiano , Lorenzi Marco , Oxtoby Neil P. , Alexander Daniel C. , Frisoni Giovanni B. , Redolfi Alberto 
Published: December 2020

AbstractBackgroundUnderstanding the path that leads from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) provides insights into dementia pathophysiology and can inform patient stratification in clinical trials. Our objective is to train statistical computational models for estimating an average disease trajectory to better understand how patients evolve on the basis of biomarkers of from the ADNI population, then validate the model on MCI subjects from the PharmaCog cohort.MethodThe disease trajectory was built via a Gaussian Process Progression Model (GPPM) (Lorenzi et al. 2017, DOI: 10.1016/j.neuroimage.2017.08.059) trained on longitudinal biomarker data from 338 subjects in the ADNI database who had converted from MCI to AD at the time of writing. Biomarkers related to cognitive scores, cerebrospinal fluid and T13D magnetic resonance imaging were used to build the disease model. Validation was performed by staging 139 MCI subjects from the PharmaCog database, 20 of whom progressed to AD, along the progression model timeline. Only baseline cross sectional measures of biomarkers were used to stage PharmaCog subjects in order to simulate clinical settings. Measures of sensitivity, specificity, balanced accuracy and area under curve (AUC) were used to measure the staging performance.ResultThe staging of PharmaCog subjects shows a clear separation between MCI stable (sMCI) subjects and MCI progressors (pMCI) on the disease timeline. On average, sMCIs were staged at year 72.7±3.6 while pMCIs are staged 3 years later (p‐value<0.01) at year 75.5±2.8. Classification of sMCI vs pMCI subjects returned a sensitivity equal to 0.68, specificity equal to 0.85, balanced accuracy equal to 0.77 and the ROC curve (Figure 1) had AUC equal to 0.75.ConclusionWe identified MCI converters to AD in a clinical data set (PharmaCog) using a data‐driven computational model of AD progression trained on research data (ADNI). Classification performance was comparable to other data‐driven tools (Young et al., 2014, DOI: 10.1093/brain/awu176), but performed in a more challenging clinical setting. This validates the staging efficacy of such models and shows their utility for future application in healthcare and clinical trials.
A novel interaction between AD risk genes synaptojanin 1 and reticulon‐3 potentially impacts synaptic function and endo‐lysosomal trafficking during disease development and progression
Authors: Cai Dongming , Huang Min , Cao Jiqing , Hou Jianwei , Zhu Li , Zhang Larry , Pero Adriana , Guo Lei , T.C.W. Julia , Zhong Minghao , Goate Alison M. , Zhang Bin , Yan Riqiang 
Published: December 2020

AbstractBackground
APOE4 is the strongest genetic risk factor for developing sporadic AD with Aβ‐dependent and Aβ‐independent effects on disease pathogenesis. However, molecular signaling mechanisms underlying the detrimental effects of APOE4 on synaptic and cognitive function are not fully elucidated.MethodsWe integrated large‐scale human postmortem RNA expression datasets from the AMP‐AD consortium with a total of 1448 human postmortem brain samples representing 5 different brain regions from hundreds of LOAD patients and non‐demented subjects to perform multiscale network analysis. Gene‐regulatory networks for female and male AD were reconstructed and modules with different functional categories and cellular specificity were identified for each network and rank‐ordered based on their relevance to LOAD pathology. The modular differential connectivity and key driver analysis were then performed to identify key drivers with sexually dimorphic expression patterns or differentially respond to APOE genotypes between sexes.ResultsIn this study, we identified synaptojanin 1 (synj1), a PIP2‐degrading enzyme with functional roles implicated in AD pathogenesis by our laboratory and others, as a key driver in AD networks that is associated with key regulators of synaptic function such as reticulon 3 (RTN3). The protein expression of both synj1 and RTN3 is increased in human and mouse brains of APOE4+
carriers. We have also detected the interaction between synj1 and RTN3 in whole brain lysate and synaptosomal fraction through co‐IP that is modified by APOE genotypes and AD status. In addition, we observed enlarged lysosomes in APOE4/4 iPSC‐derived neuron and astrocyte co‐culture when compared to APOE3/3 counterparts. Down‐regulation of synj1 or over‐expression of RTN3 dramatically ameliorated these phenotypes.ConclusionsBased on these findings, we propose a model that the interaction between synj1 and RTN3 under physiological conditions may play important roles in regulation synaptic function and endo‐lysosomal trafficking. In APOE4+
brains, increased synj1 levels may impair intracellular trafficking of RTN3 from tubular ER to vesicular compartments leading to RTN3 retention within ER tubules with reduced distribution to downstream compartments which may contribute to reduced RTN3 degradation, compromised ER integrity, and impaired synaptic function and endo‐lysosomal trafficking.