bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise as a strategy to prevent APOEε4‐dependent phenotypes
Authors: Foley Kate E. , Diemler Cory , Garceau Dylan , Moore Annah M. , Hohman Timothy J. , Sasner Michael , Howell Gareth 
Published: December 2020

AbstractBackgroundHuman data suggest cerebrovascular dysfunction precedes and exacerbates Alzheimer’s disease (AD). APOEε4 contributes to cerebrovascular decline with age, and APOE status interacts with angiogenesis pathways including the VEGF family to modify cognitive decline. However, the precise nature of this relationship is not known. Research suggests that running provides substantial health benefits that reduce risk for AD. Previous data from our lab showed that, transcriptionally, cerebrovascular processes such as vascular remodeling and angiogenesis terms can be altered short term running in young mice. Here, we are combining human and mouse studies to (i) understand the relationship between APOE status and the VEGF pathway in AD, and (ii) determine whether the effects of exercise on the cerebrovasculature are modified by APOE status.MethodTo assess cerebrovascular health, we took several approaches: (i) transcriptional profiling, (ii) immunofluorescence of basement membrane, and (iii) immunofluorescence of leakage (fibrin). To assess exercise and metabolic differences, B6.APOEε4/ε4 (risk) and B6.APOEε3/ε3 (neutral) mice were run from 1‐4 months (mo) and 1‐12mos, as well as metabolic phenotyping including circulating plasma lipid levels, food intake, water loss, running speed, and gas exchange. Heterozygous B6.APOEε3/ε4 mice are included to evaluate the potential hypomorphic/ hypermorphic function of the APOEε4 allele on cerebrovascular health. Human data from ROSMAP and ADNI cohorts is being compared to mouse data.ResultCerebrovascular dysfunction was evaluated in 2mo and 12mo B6.APOEε3/ε3 and APOEε4/ ε4 mice for basement membrane coverage and fibrin leakage which revealed an increase in COL4 and increased leakage, in 12mo female APOEε4/ε3 compared to B6.APOEε3/ε3 mice. Analysis of 1‐4mo running data showed no transcriptional evidence that the cerebrovasculature was altered in young APOEε4 or APOEε3 carriers, suggesting longer term interventions are necessary. Human data shows patients that suffer a more severe cognitive decline have increasing levels of angiogenesis markers in the brain and blood. Our ongoing work aims to identify the mechanism between APOEε4 and angiogenesis/cerebrovascular integrity.ConclusionRecreated APOEε4mice recapitulate age‐dependent cerebrovascular deficits however running at a young timepoint will likely not affect cerebrovascular health. Longer term studies are underway to determine whether chronic running mitigates age‐dependent effects of APOEε4.
Functional characterization of an Alzheimer disease‐associated deletion in SORL1
Authors: Dykxhoorn Derek M. , Simon Shaina A. , Kunkle Brian W. , Cuccaro Michael L. , Vance Jeffery M. , Cukier Holly N. , Pericak‐Vance Margaret A. 
Published: December 2020

AbstractBackgroundOver 20 genetic loci have been consistently associated with Alzheimer disease (AD) with accumulating evidence pointing to alterations of the endolysosomal pathway as playing key roles. The sortilin‐related receptor 1 (SORL1) gene has been associated with AD through multiple genetic studies and has been suggested to function by guiding APP to the endocytic pathway. We recently identified a family with multiple AD affected individuals that bear a single base pair deletion (g.4292delG) predicted to result in a frameshift alteration and early termination of the protein (p.Cys143Ser*1). Previous studies have implicated SORL1 variants in AD pathogenesis, but it remains unclear how this deletion impacts SORL1 protein function and AD development.MethodInduced pluripotent stem cells (iPSC) lines were developed to examine the cellular and molecular consequences in neuronal and glial cell (astrocytes and microglia) populations, which can otherwise only be collected postmortem. Each iPSC line generated was validated for pluripotency through immunocytochemical staining and shown to be negative for any large‐scale chromosomal abnormalities via karyotyping. The patient iPSC lines and control lines were differentiated into cortical neurons and glia cells for functional analyses, including amyloid beta production and uptake, vesicular trafficking, and neurite outgrowth.ResultWe have generated iPSC lines from two individuals bearing this deletion in SORL1 and have confirmed their pluripotency by immunocytochemistry. These cells were differentiated into cortical neurons whose identity was confirmed by staining for forebrain markers. The SORL1 variant bearing cortical neurons showed enlarged endosomes compared to the neurons derived from control iPSCs, as measured by the staining with an anti‐RAB5 antibody and fluorescent microscopy. In addition, the SORL1 deletion bearing neurons showed an upregulation of pathogenic amyloid beta 42 measured by ELISA. Glial cells have emerged as pivotal players in the maintenance of brain homeostasis. Therefore, we will assess the functional impact of this deletion of SORL1 in microglial cells and astrocytes.ConclusionIn summary, our results support that the p.Cys143Ser*1 variant is indeed pathogenic. iPSC‐derived neurons and glia cells bearing the deletion in SORL1 p.Cys143Ser*1 variant shows cellular deficits associated with AD pathology which could serve as new avenues for therapeutic development.
Aortic pulse wave velocity as a predictor of cognitive decline in older adults
Authors: de la Torre Paola Garcia , Almeida‐Gutiérrez Eduardo , Torres‐Rosales Jorge , Sanchez‐Garcia Sergio , Cuadros‐Moreno Juan , Garcia‐Dominguez Juana A. 
Published: December 2020

AbstractBackgroundGlobal aging has caused a demographic transition that has had an effect on health systems all over the world. Together with dementia, cardiovascular disease is a common health concern in older adults and is the first cause of death globally. The contribution of an unhealthy vascular system to the development of dementia has been stated before.MethodUsing a cross‐sectional analysis, we performed vascular non‐invasive measurements in older adults with (n=101) or without (n=65) detectable cardiovascular disease using a commercial device. All subjects were evaluated for cognitive decline.ResultsWe found 54.83% cognitive impairment in the free‐cardiovascular disease group and 41.58% for the cardiovascular disease group. Aortic pulse wave velocity was significantly higher in patients with cognitive decline (p<0.05) independently of their cardiovascular health. However, a higher wave return velocity (p<0.05) and aortic wave velocity (p<0.05), and a lower augmentation index (p<0.001) was found in older adults with cardiovascular disease compared to cardiovascular disease free subjects.ConclusionAortic pulse wave velocity is associated with cognitive decline regardless of the presence of cardiovascular disease. Furthermore, subjects with cardiovascular disease have higher wave return velocity and aortic wave velocity, and lower aortic pulse wave velocity.
Increased 18F‐flortaucipir load correlates with changes in MEG functional connectivity and network topology, as well as oscillatory slowing
Authors: Schoonhoven Deborah N. , Coomans Emma M. , van Nifterick Anne M. , Ossenkoppele Rik , Scheltens Philip , Stam Cornelis J. , Golla Sandeep S. V. , Arjan Hillebrand , Van Berckel Bart N. M. , Gouw Alida A. 
Published: December 2020

AbstractBackgroundRecent fMRI studies have provided evidence that tau proteins may spread through the brain in stereotypical patterns following functional connections. However, fMRI is an indirect measure of neuronal activity, and has limited temporal resolution, contrary to magnetoencephalography(MEG). We aimed to investigate whether changes in neuronal activity, functional connectivity and network organization mirror regional tau retention in (preclinical) Alzheimer’s disease(AD), using MEG and in‐vivo 18F‐flortaucipir (tau) PET.MethodsTwenty participants with AD pathology according to the ATN‐criteria (CSF‐Aβ42 and/or amyloid‐PET) were recruited from the Amsterdam Dementia Cohort, classed as subjective cognitive decline (SCD; n=10) and probable AD dementia (n=10), Table‐1. Participants underwent dynamic 130‐minutes 18F‐flortaucipir PET, and 10‐minutes eyes‐closed, task‐free 306‐channel MEG recordings. Neuronal activity and 18F‐flortaucipir non‐displaceable binding potential(BPND) were reconstructed for 52 regions‐of‐interest(ROIs) in an adjusted version of the probabilistic Hammers atlas. Associations between 18F‐flortaucipir BPND and MEG spectral measures (peak frequency, relative delta(0.5‐4Hz); theta(4‐8Hz); alpha(8‐13Hz); beta(13‐30Hz); gamma(30‐48Hz) power); connectivity (volume conduction‐corrected amplitude envelope correlation(AEC‐c) in delta, alpha and beta band); and network measures (minimum spanning tree betweenness centrality(BC)) were investigated using generalized estimating equation(GEE) models, for SCD and AD dementia combined. To investigate possible group effect, the GEE was repeated using only the AD dementia‐group.ResultIncreased regional 18F‐flortaucipir binding correlated strongly with oscillatory slowing in both the total sample and AD‐group, reflected by negative correlations with peak frequency, relative alpha and beta power, and positive correlations with relative delta and theta power, most pronounced in parietal and occipital regions (Fig‐1A+B). Regional 18F‐flortaucipir binding correlated with loss of connectivity for both groups mainly in the occipital regions (average β=‐0.677±0.16, β=‐0.660±0.23 resp.) for the beta band, Fig‐2A+B. The delta band showed an opposite effect in frontal and occipital regions. Higher 18F‐flortaucipir binding was associated with lower centrality in temporal (delta) and subcortical regions (alpha, beta), and higher centrality in the parietal region (alpha), Fig‐2A+B.ConclusionWe provide putative evidence that increased regional 18F‐flortaucipir binding associates to reduced neuronal activity, as well as loss of connectivity in higher frequency bands, which could be replicated in a separate AD analysis. Furthermore, tau deposition seems to be related to damage to highly connected hub nodes.
Targeting the Moesin‐CD44 pathway for therapeutic intervention in Alzheimer’s disease
Authors: Katis Vittorio , Bradshaw William , Betarbet Ranjita , Jimenez‐Antunez Carmen , Seyfried Nicholas T. , Slakman Belinda , Mulhern Christopher , Guie Marie‐Aude , Keefe Anthony , Guilinger John , Zhang Ying , Huguet Christelle , Levey Allan I. , Brennan Paul E. , Mangravite Lara M. , Gileadi Opher ,   The Open‐AD Consortium
Published: December 2020

AbstractBackgroundInvestigation of the Alzheimer’s Disease (AD) brain proteome, along with weighted co‐expression network analysis, revealed a module enriched with proteins involved in inflammation (PMID: 27989508). This module progressively increases in brains from Controls to Asymptomatic AD to those with Symptomatic AD. Moesin (MSN) and CD44 emerged as key inflammation module hub proteins. MSN is a cytoskeletal protein with roles in focal adhesion‐mediated cell motility; CD44 is a transmembrane receptor that interacts with MSN. This project aims to develop chemical tools to disrupt this pathway.MethodTo investigate the AD‐relevant distribution of MSN, tissue sections and cells were stained with MSN‐specific antibodies as well as with Iba1, 4G8 and pHF‐Tau antibodies. Purified FERM domains of MSN and EPB41L3 were produced in E. coli and co‐crystallized or soaked with ligands after crystallization. The CD44 ectodomain was expressed in bacteria and refolded or secreted from HEK293 cells.DNA‐encoded library screens were performed as described (http://www.x‐chemrx.com/our‐science/).ResultMSN‐staining in cortical human brain sections localised to endothelial cells and microglia‐like cells. MSN‐positive cells also stained for microglia‐specific marker, Iba1. In AD brains, MSN‐positive microglia‐like cells were present around amyloid plaques and tangle‐like structures. These immunohistochemical studies confirmed the association of MSN with AD pathology. Co‐crystal structures of Moesin and the related FERM protein EPB41L3 revealed the binding mode of the intracellular tail of CD44 to Moesin. This binding interaction was then used to develop HTRF‐based assays for high‐throughput screening for molecules that disrupt the CD44‐MSN interaction. In parallel, a crystal‐based fragment screen using EPB41L3 identified binding pockets and initial hits. Hits and chemical staring points will be further developed with the Open‐AD Medicinal Chemistry core at UNC. To identify inhibitors of CD44 ectodomain binding to hyaluronic acid we screened DNA‐encoded libraries. The screens identified micromolar hits which are being further developed, aiming to obtain potent brain‐penetrant inhibitors of CD44.Conclusion(1) Moesin expression is associated with AD pathology. (2) The CD44‐Moesin signalling axis was targeted for potential points of intervention. (3) We have developed the assays, structural biology and chemical starting points to develop small‐molecule inhibitors of the CD44 ectodomain and the CD44‐MSN interaction.
Validation of a simplified tissue‐to‐reference ratio measurement using SUVR for the assessment of synaptic density alterations in Alzheimer’s disease using [11C]UCB‐J PET
Authors: O'Dell Ryan S. , Naganawa Mika , Toyonaga Takuya , Young Juan , Dahal Rabin , Singh Edward , Waheed Aisha , Banks Emmie R. , Harris Joanna E. , Chen Ming‐Kai , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H. , Mecca Adam P. 
Published: December 2020

AbstractBackgroundSynaptic density PET is an emerging technology with potential as a biomarker for tracking disease progression and therapeutic efficacy in studies of Alzheimer's disease (AD). Simplified methods of image acquisition and quantification would facilitate the use of synaptic density imaging in multicenter longitudinal studies. Therefore, we validated a simplified tissue‐to‐reference ratio method using standardized uptake value ratios (SUVR) for estimating synaptic density using [11C]UCB‐J PET.Method[11C]UCB‐J binding was measured in 31 participants with early AD and 16 cognitively normal (CN) participants aged 55‐85 years. All participants underwent 90 minute dynamic PET scans on the HRRT after bolus injection of [11C]UCB‐J. Parametric images of binding potential (BPND
) were generated using SRTM2 (0‐60 minutes) with a centrum semiovale reference region and converted to distribution volume ratios (DVR) with a cerebellum reference region. Parametric images of SUVR were generated by summing frames from 30‐60 or 60‐90 minutes and normalizing to the cerebellum. Regional group differences were assessed using unpaired t tests and Cohen’s d, while associations between DVR and SUVR were assessed using Pearson’s correlation.ResultWidespread reductions in cortical and subcortical synaptic density were observed in AD (vs. CN) participants using measures of DVR, SUVR30‐60min
, and SUVR60‐90min
. In the entire sample, stronger regional correlations between measures of DVR and SUVR60‐90min
(r=0.97, p<0.00001) were observed compared to DVR and SUVR30‐60min
(r=0.91, p<0.00001; Figure 1). The correlation between DVR and SUVR60‐90min
was also stronger for within‐group correlations (DVR vs. SUVR60‐90min
r
CN
=0.97, r
AD
=0.97; DVR vs. SUVR30‐60min
r
CN
=0.90, r
AD
=0.91). The within‐region correlation between measures of DVR and SUVR60‐90min
ranged from 0.77 to 0.97 (p<0.00001) in the entire sample. Effect sizes to determine group differences in SV2A binding across all regions were highly correlated between both DVR and SUVR60‐90min
(r=0.93, p<0.00001) and DVR and SUVR30‐60min
(r=0.93, p<0.00001; Figure 2).ConclusionA simplified method of quantifying synaptic density with SUVR using a shortened (60‐90 minute) scan window and cerebellum reference region is highly correlated with measures of DVR generated with SRTM2 kinetic modeling. This simplified tissue‐to‐reference ratio methodology may be of practical use for multicenter and longitudinal studies seeking to measure synaptic density in AD.
Predicting amyloid status using remote online self‐report and cognitive assessment: The Brain Health Registry
Authors: Ashford Miriam T. , Neuhaus John , Jin Chengshi , Camacho Monica R , Fockler Juliet , Truran‐Sacrey Diana , Mackin R. Scott , Rabinovici Gil D. , Weiner Michael W. , Nosheny Rachel L. 
Published: December 2020

AbstractBackgroundThe ability to identify older adults with elevated brain amyloid beta (Ab) load can facilitate Alzheimer’s disease (AD) prodromal and preclinical trial recruitment and has possible clinical benefits. Development and validation of non‐invasive, cost‐effective methods to accurately predict brain Ab status are crucially needed. The overall goal of this study was to assess the predictive value of online, remotely‐collected information in determining Ab‐PET status. We compared the predictive performance of online measures to the performance of similar in‐clinic measures.MethodThe Brain Health Registry (BHR) is an online registry for recruitment and longitudinal assessment in cognitive aging research. In BHR participants who had an available Ab status from in‐clinic PET scans, logistic regression was used to determine the optimal combination of online variables to predict Ab‐PET (Ab+ and Ab‐) status in all participants. BHR predictors included: demographics (age, gender, education), self‐reported health information (memory concern, family history of AD, Geriatric Depression Scale (GDS) score, Everyday Cognition Scale score), and a cognitive assessment (Cogstate Brief Battery (CBB)). Area under the receiver operator curve (AUC) evaluated discrimination accuracy. The model with the highest AUC was cross‐validated using 10‐fold cross‐validation.Result354 BHR participants had available Ab data and sufficient additional BHR data (see Table 1 for participant characteristics). 48.9% of the participants were Ab+. Model accuracy ranged from AUC 0.55‐0.65 (see Table 2). The most accurate predictive model (AUC=0.65) included demographics, self‐reported health information, and CBB. In this model, GDS score, memory concern, and gender were all significantly associated with Ab status. The cross‐validated estimated AUC was 0.58, which is noticeably lower than the uncorrected estimate. In a larger cohort (n=635) of participants who did not take Cogstate, other BHR variables predicted Ab+ (AUC=0.79). The discrimination ability of our online data was comparable to studies that used similar information collected in‐clinic, with in‐clinic AUCs ranging from 0.59‐0.76.ConclusionOur results suggest that a novel, online approach can aid in the prediction of Ab status. Since online variables are low‐cost and non‐invasive, there is an advantage to using this approach to facilitate AD trial screening than prediction models that use in‐clinic measures.
The role of co‐morbid hypertension and depression on cognitive and proteomic outcomes among Mexican Americans
Authors: Large Stephanie E. , Davila Marcela , Petersen Melissa , Hall James R. , O'Bryant Sid , Davis Sandra E. , Johnson Leigh Ann 
Published: December 2020

AbstractBackgroundMedical comorbidities are commonly associated with poorer cognition. Hypertension and depression are common comorbidities linked to cognitive decline and Alzheimer’s disease (AD). Mexican Americans experience higher rates of these medical comorbidities and also present with cognitive decline at younger ages as compared to their non‐Hispanic White counterparts. Increased work has expanded to look at reasons for increased risk for neurodegenerative conditions such as AD specifically among this population. The purpose of this study was to examine the role of co‐morbid hypertension and depression on cognitive and proteomic outcomes.MethodData from 548 Mexican Americans (415 normal control, 133 MCI/AD) was collected from a community based epidemiological study of aging. The average age was 61 and the average education was 7.7 years. Participants were stratified into 4 groups: no hypertension or depression (N= 101), hypertension only (N= 218), depression only (N=59), and comorbid hypertension and depression (N=170). One‐way ANOVAs were utilized to examine group differences in cognitive performance and proteomics. Cognition was assessed via WMSIII Logical memory 1 & 2, Trails A/B, EXIT, and MMSE. Biomarkers of inflammation (serum TNFα, IL5, IL6, IL7, IL10 and CRP) and neurodegeneration (plasma Aß42/ Aß40, Tau, NFL) were analyzed. A logistic regression was calculated with normal control versus MCI/AD as the outcome variable and comorbid condition, education and age as predicting variables.ResultIn normal controls, comorbid hypertension and depression was significantly associated with poorer executive and global cognitive function; and this comorbidity increased risk of MCI/AD diagnosis (OR= 1.950; 95/5 CI= 1.23‐3.08). Among normal controls, the comorbid group was found to have significantly higher levels of NFL (p<0.032) and IL6 (p<0.018) than the depression only group. Among those with MCI/AD, the comorbid group had significantly higher NFL levels (p<0.002) than the neither condition group.ConclusionThe results of the study demonstrated that comorbid hypertension and depression was related to poorer cognitive functioning and increased risk for cognitive impairment among Mexican Americans. Findings support that medical conditions likely influence biomarkers of inflammation and neurodegeneration, which lends support for a precision medicine approach to treating MCI and AD specifically among minority populations.