bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐wide association analyses identify genes modifying age‐at‐onset of Alzheimer’s disease
Authors: Martin Eden R. , Sun Shuming , Slifer Susan H. , Naj Adam C. , Gao Xiaoyi R. , Li Yi‐Ju ,   Alzheimer Disease Genetics Consortium (ADGC)
Published: December 2020

AbstractBackgroundSeveral studies have attempted to identify genes for age‐at‐onset (AAO) of dementia symptoms in Alzheimer’s disease (AD) through genome‐wide linkage (Daw et al. 1999, Li et al. 2002, Choi et al. 2011) and genome‐wide association studies (Kamboh et al. 2012, Naj et al. 2014). Naj et al. conducted a meta‐analysis of 14 datasets from the Alzheimer’s Disease Genetics Consortium (ADGC) with genotype imputation to HapMap2. Using an expanded set of ADGC cohorts, we re‐examined AAO using higher‐quality genome‐wide imputation data and pooled‐data analysis instead of meta‐analysis to identify novel genetic contributors to AAO of AD.MethodsWe combined data from 20 non‐Hispanic white prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data were imputed to the Haplotype Reference Consortium (HRC) r1.1 reference panel using the Michigan Imputation Server and consistent quality control applied to each dataset, after which genotype data were merged across datasets using QCTOOL and GTOOL. We performed case‐only association analyses for log10(AAO) using multivariable linear regression with covariate adjustment for sex, cohort, and principal components capturing population substructure, and then conducted analyses conditioning on dosage of APOE ε4 alleles. Variants with P < 10−5 from conditional analyses were re‐analyzed using linear mixed modeling treating cohort as a random effect.ResultsWe used 9,228 AD cases, including 5,307 females (57.4%) with mean (SD) AAO of 74.2(7.7) years. In addition to the APOE region, which reached genome‐wide significance (P < 5 × 10−8), we observed strong novel associations with variants in NTM (encoding neurotrimin) on chr11q25 (rs117589002, P = 1.24 × 10−7) and in an intergenic region on chr3p22.3 (Pmin
= 1.89 × 10−7). Other AAO loci previously identified in the smaller ADGC dataset (Naj et al 2014) remained nominally significant. After adjusting for APOE ε4, thirty‐two regions showed suggestive association (P < 10−5), with chr3p22.3 and NTM remaining the top loci. Chromosome 11q25 includes a known AD linkage region (Blacker et al. 2003). In addition, NTM variation has been found to be correlated with cognitive function tests (Liu et al. 2007) and intelligence (Pan et al. 2010).ConclusionsIn an expanded ADGC dataset, we confirmed AAO associations in the APOE region and observed evidence for potential novel AD AAO loci including NTM.
Reduced memory and executive functioning significantly relates to participation in early phase clinical research in Alzheimer's disease
Authors: Park Lovingly , Gertsik Lev , Mendoza Zyanya , Morris Lydia , Aguilar Claudia , Sherman Molly , Semenova Svetlana , Jhee Stanford 
Published: December 2020

AbstractBackgroundThe patient’s decision to enroll in clinical research is hampered by level of impairment, the need for a study partner, inclusion/exclusion criteria as well as factors related to the study design and trial procedures. These are exacerbated in early phase since the objectives center on safety and tolerability, without explicit benefit for the patient to participate. With the scientific advancements in AD, the protocols are increasingly complex with procedures involving CSF, pharmacokinetic sampling, and clinical endpoints. This study delineates the degree to which cognition may influence a patient’s decision to participate in clinical research.MethodPatients were recruited a memory clinic at Parexel Early Phase Clinical Research Unit. Referrals come from their treating physicians, community outreach, and the research programs if there is a need for a diagnostic evaluation prior to their screening visits. We included a sample of healthy older adults (HNE; n=37, age=65.46, education=15.05), Mild Cognitive Impairment (MCI; n=54; age= 70.78, education= 14.20), AD (n=75, age=77.37, education=13.27), and other neurologic conditions (n=16; age=62.38; education=12.86). A binary logistic regression was used, with interested and not interested in research participation as the DV. The RBANS served as the index for cognition, COWAT and TMT B were the indices for executive functioning. Patients were provided descriptions of the types of procedures involved and a summary of the risks and benefits of participating, before they were asked about their interest in participation.ResultThere were differences in cognition across all diagnostic groups with the healthy elderly performing better across all tests than the others (p<.05) and they were also more likely to participate than others. Results of the logistic regression showed that the relationships among list learning (χ2 =4.97, p<.05), recognition (χ2 =8.03, p<.05), and letter fluency (χ2 =4.11, p<.05) were significantly related to participation.ConclusionFindings show that cognition, particularly in initial learning and executive functioning, predicts whether patient’s decision to participate. This is not surprising given the complexity of the information presented to the patient that are associated with most early phase research studies. Careful and tailored conversations about research studies are needed to facilitate recruitment.
Hypertension accentuates reductions in CSF Aβ42 in elderly depressives
Authors: Pomara Nunzio , Bruno Davide , Reichert Chelsea , Lee Sang Han , Sarreal Antero , Hernando Raymundo , Ramos‐Cejudo Jaime , Zetterberg Henrik , Blennow Kaj 
Published: December 2020

AbstractBackgroundHypertension (HTN) is a well‐established risk factor for Alzheimer’s disease (AD). Observations from animal and human PET studies indicate that HTN may be mechanistically linked to AD by increasing brain Aβ deposition which may represent the first pathogenetic event in the onset of AD dementia. For example, a diagnosis of HTN, has been associated with increased brain Aβ on PET imaging in humans. HTN is also common in late‐life depression (LLMD), a disorder which is also associated with increased risk for AD and altered Aβ dynamics consistent with increased brain Aβ burden including reductions in CSF Aβ42. Our group first reported a reduction in CSF Aβ42 which was unrelated to APOE status. However, the neurobiological mechanisms for the association between LLMD and altered Aβ metabolism are not fully understood and might involve co‐morbid vascular factors such as HTN. These considerations prompted us to examine the relationship between LLMD, HTN and CSF AD biomarkers in a cohort of non‐demented elderly.MethodsCSF was obtained from 47 individuals (28‐LLMD and 19 ‐controls) 60 years or older with MMSE>28 and without significant white matter hyperintensities. A general linear model was used to compare the effect of hypertension status (HTN; Hypertensive or Not Hypertensive) and diagnosis (Dx; LLMD or control) on baseline AD biomarkers (Aβ42, Aβ40).ResultsWe found that controls without HTN (mean=361 pg/ml) had sig. higher CSF Aβ42 than LLMD without HTN (mean=220 pg/ml; Tukey adj. p‐value = 0.18) and LLMD with HTN (mean=202 pg/ml; Tukey adj. p‐value = .031) given the significant interaction of HTN and Dx (p=0.05). There was also a main effect of HTN on Aβ40 (p=.025).ConclusionsThese preliminary results suggest that hypertension and LLMD are independently associated with reductions in CSF Aβ42 and that co‐morbid HTN may accentuate its reduction in LLMD. Thus, more effective treatment of depression and HTN may attenuate the increased risk for AD associated with these disorders.
Physical activity patterns in healthy and cognitively impaired older Chileans using wireless‐enabled wearable technology devices
Authors: Rogers Nicole , Lazcano Joaquin , Herrera Sebastian , More Jamileth , SanMartín Carol D , Bennett Magdalena , Romero Cesar , Grinspun Noemí , Valdés Jose L , Behrens María Isabel 
Published: December 2020

AbstractBackgroundIncreasing physical activity (PA) benefits cognition in older adults, both healthy and cognitively impaired. However, there is a lack of knowledge in the baseline amount and type of PA performed by this age group, especially in underrepresented populations. Furthermore, previous studies with other populations have almost exclusively focused on self‐reported and caregivers' questionnaires, which are considered limited tools for assessing PA and exercise.MethodWe recruited 77 people between the ages of 60 and 91 (average: 72.7 years) from different neighborhoods is Santiago de Chile, both cognitively healthy and with varying degrees of cognitive impairment. They underwent gait and neuropsychological evaluations and a thorough interview and neurological exam. Their PA was registered for a month with the use of a smart wristband activity monitor (Fitbit Alta HR). Daily steps, time spent inactive (sedentary activity, SA), in light physical activity (LPA), and moderate to vigorous physical activity (MVPA) were determined with the help of the algorithms provided by Fitbit.ResultHealthy participants (HP)(n=53), amnestic mild cognitive impaired (aMCI) patients (n=14), and mild Alzheimer disease (AD) patients (n=10) averaged 6700 steps a day (HP=7015, aMCI=6700, AD=4910). There were no statistically significant differences in mean daily steps between the groups, nor in time they spent in sedentary activity, LPA, and MVPA. There were no significant differences between sexes for these variables. HP, aMCI, and AD patients registered an average of 140%, 220% and 250% more time in SA than what they had previously self‐reported, respectively; interestingly, healthy participants self‐reported higher time spent in SA than the cognitively impaired but average higher means of daily steps, and more time in LPA and MVPA. There was a significant inverse correlation between age and mean daily steps, and with LPA.ConclusionThe use of wireless wearable‐technology offers a unique opportunity to study to role of PA patterns in other non‐transmissible diseases in healthy and cognitively impaired older individuals. More focus should be put in the prevention of sedentarism and the promotion of PA and exercise since it offers an approachable and measurable way of preventing cognitive decline, as well as shedding light on new biological mechanisms of neuroprotection.
Tau pathology spread in white matter pathways in atypical Alzheimer’s disease
Authors: Eckbo Ryan , Dickerson Brad C. , Makris Nikos , Collins Jessica A. 
Published: December 2020

AbstractBackgroundStudies on animal models suggest that pathologic tau propagates along axons in a prion like manner, however there's limited evidence for this transneuronal spread in patients. In the current study we tested this hypothesis in a group of patients with heterogeneous clinical presentations of early Alzheimer's disease (AD) by examining the relationship between focal tau burden and the integrity of connected white matter pathways. We focused our analyses on the middle longitudinal fascicle (MdLF) because it connects several regions that are vulnerable to early tau accumulation across clinical presentations of AD.Method25 patients diagnosed with AD (14 PCA, 11 PPA, and 3 with amnestic MCI) underwent a tau (18F‐AV‐1451) PET (HR+ Siemens) scan, a T1‐weighted 3D MEMPRAGE scan, and a diffusion tensor imaging (DTI) (64 directions) scan. PET data were processed with FreeSurfer v6.0's PetSurfer pipeline with partial volume correction (PVC) and the DTI data were processed using UKF tractography. The left and right MdLF were defined in each patient and mean diffusivity (MD) was extracted as a measure of reduced microstructural integrity. Pearson’s r correlations were used to assess the relationship between MdLF MD and tau burden (18F‐AV‐1451 SUVR) in brain regions connected to the MdLF.ResultMean MD in the MdLF showed a positive correlation with tau uptake in both hemispheres in precuneus (left: r=0.47, right: r=0.48), superior temporal gyrus (STG) (left: r=0.45, right r=0.54), and supramarginal gyrus (SMG) (left r=0.50, right: r=0.51), all ps < .05, such that patients with higher tau burden in these regions had reduced MdLF microstructural integrity. There was no relationship between tau burden in the temporal poles and MD in the right or left MdLF.ConclusionOur results demonstrate that focal tau accumulation is associated with reduced microstructural integrity in connected white matter pathways. These results are consistent with accumulating research suggesting that pathologic tau proteins may propagate along axons from one brain region to another.
Validating the use of spatially resolved spectroscopy to demonstrate improvement of cerebral blood flow following external counterpulsation treatment in patients with mild cognitive impairment or Alzheimer’s disease
Authors: Helfgott Jonathan S. 
Published: December 2020

AbstractBackgroundThere is a strong correlation between Alzheimer’s Disease (AD) and poor cerebral blood flow (CBF). RenewTM NCP‐5 is an FDA‐cleared, external counterpulsation ECP device, which chronically improves coronary and peripheral vascular hemodynamics, and may provide the same benefit for cerebral perfusion and cognitive function. Accurate measurements of CBF, such as arterial spin labelling MRI, can be extremely costly, and alternative solutions may be less accurate. The moorVMS‐NIRS uses the established spatially resolved spectroscopy technique to measure tissue oxygen saturation (SO2) and relative concentrations of oxygenated haemoglobin (oxyHb) and deoxygenated haemoglobin (deoxyHb) in human tissueMethodA subset analysis of patients enrolled in the RenewTM NCP‐5‐1001 research protocol (NCT03721705), will be monitored with the VMS‐NIRS device over the course of two 60 minute treatments, first during randomization then during week 24, which mark the start and end of their treatment regimen, respectively. The moorVMS‐NIRS measures oxygenation using a probe which is placed in contact with the skin over patients’ temples. Each probe consists of a detector head which contains two identical photodiodes and emitter head which contains near infrared LEDs emitting light at approximately 750 nm and 850 nm. To ensure replicable measurements from randomization to week 24. A BraiNet cap is used to mark the probe location.ResultIndividual patient data will be analyzed using both the individual patient as their own control (at randomization versus week 24) as well as a therapeutic efficacy comparison between patients randomized to the treatment group versus sham therapy. Acute and chronic changes will be monitored as continuous measurements will be taken during each treatment session. Arterial spin labeling MRI will be measured within 3 weeks of randomization and again within 3 days of the week 24 visit.ConclusionMRI results may be able to corroborate and further validate the use of the moorVMS‐NIRS device as an accurate, cost‐effective measurement to detect changes in levels of brain oxygenation for future trials.
Influence of rural vs urban county composition on AD neuroimaging biomarkers
Authors: Risacher Shannon L. , Wang Sophia , West John D. , Deardorff Rachael , Gao Sujuan , McDonald Brenna C. , Apostolova Liana G. , Saykin Andrew J. 
Published: December 2020

AbstractBackgroundIndividuals from rural and exurban areas are understudied in the context of AD, as academic institutions are generally located in urban areas. We evaluated whether individuals from rural (>50% rural), exurban/suburban (10‐50% rural), and urban (<10% rural) areas, based on population density in each county, differed in A/T/N biomarkers of AD.MethodAn ADRC‐based sample of 142 participants was studied with amyloid PET ([18F]florbetaben or [18F]florbetapir) and 3T MRI; 95 also underwent tau PET ([18F]flortaucipir). Participants were divided into groups by county composition, as described above. Amyloid PET scans were converted to Centiloid values (CL), and cortical CL was extracted. MRIs were processed using FreeSurfer v6 to extract temporal lobe cortical thickness. Tau scans were processed and temporal lobe SUVR was extracted. One‐way ANCOVAs were used to evaluate the relationship of county composition to A/T/N measures, covaried for age, sex, race/ethnicity, education, diagnosis (cognitively normal (CN), subjective cognitive decline (SCD), MCI, or AD), and ICV (MRI only). Chi‐square tests were used to assess the relationship of county composition and diagnosis, as well as amyloid positivity (CL>20).ResultOf the 142 individuals, 9 were from rural counties, 35 were from exurban/suburban counties, and 98 were from urban counties. No difference in diagnosis by county composition was observed. Participants from rural counties were more likely to be Aβ+ (Figure 1A, p<0.001) than participants from other county compositions. Cortical CL was greater in individuals from rural counties and exurban/suburban counties relative to those from urban counties (Figure 1B, p=0.032). Finally, those from rural and exurban/suburban areas showed greater temporal lobe atrophy relative to urban counties (Figure 1C; p=0.019). No effects of county composition on tau were observed.ConclusionOur findings suggest that individuals from rural or exurban areas may have higher AD pathology on imaging. One limitation of this initial ADRC‐based study was the small sample size of rural participants. Future population neuroscience studies designed to recruit rural individuals into neuroimaging studies are needed to fully evaluate the role of rural versus urban residency on AD biomarkers.
Altered expression of mitochondrial genes involved in energy production and mitochondrial biogenesis is related to an increase in inflammatory factors associated with Alzheimer’s disease
Authors: Castora Frank J. , Slocum Jayne A. , Knoble Joseph A. , Kerns Kimberly A. , Hitefield Naomi L. , Gershon Blake , Shugoll Jason , Coleman Randolph A. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease that presents with symptoms such as cognitive impairment and a decline in memory. While often characterized by amyloid plaques and neurofibrillary tangles, there are a number of factors that play a role in this chronic disease. Recent studies have shown that mitochondrial function, and particularly, cytochrome oxidase (COX) activity is decreased in AD, disrupting mitochondrial energy production and potentially contributing to neurodegeneration. More recently, studies have indicated that inflammation plays an important role in the development of neurodegenerative diseases such as AD. Here, we analyzed changes in expression of 162 genes involved in mitochondrial energy production and biogenesis from 16 brain samples (11 AD and 5 age‐matched controls) and examined our findings through the lens of correlating any mitochondrial gene changes with inflammation processes.MethodTotal RNA was isolated from 80‐180 mg of frozen brain tissue from the 16 samples. Total RNA was quantified and assessed for purity using Nanodrop and Bioanalyzer analysis. cDNA was prepared and applied to the Human Mitochondrial Energy Metabolism and the Mitochondria RT² Profiler™ PCR Arrays. The qPCR data was then analyzed using Qiagen RT2 Profiler PCR Array Data Analysis version 3.5. The fold regulation and p‐value data was input into Ingenuity Pathway Analysis software to identify biologically important networks and pathways affected by AD.ResultThree energy metabolism genes – ATP4A, ATP6VIG3, and NDUFA8 – were found to be strongly up‐regulated in AD vs control brains while 6 mitochondrial biogenesis genes – UCP3, TIMM22, SLC25A21, SLC25A23, SLC25A25 and TIMM9 – were found to be strongly downregulated. Furthermore, two transcriptional regulators, RICTOR and KDM5A were activated while upstream regulators PPARGC1A and RB1 were inhibited in the AD vs control samples. The observed changes in mitochondrial gene expression in our data set were associated with neurodegeneration and inflammatory response networks.ConclusionGene expression data revealed an overall increase in inflammatory activity in AD brains compared to control brains. Further studies are needed to determine the clinical application of these findings, as an anti‐inflammatory approach to AD directed at mitochondrial genes/proteins could potentially slow the development or onset of the disease
AXL activation leads to reduced amyloid plaque deposition in APP/PS‐1 mice
Authors: Owlett Laura , Olschowka John A , Elliott Michael R. , O'Banion M. Kerry 
Published: December 2020

AbstractBackgroundMicroglia, the immune cells of the brain, play seemingly antagonistic roles in the Alzheimer’s disease (AD) brain. On one hand, microglia contribute to clearance of amyloid beta (Aβ) plaques via phagocytosis. On the other hand, activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis. Axl, a member of the TAM receptor family, is increased on microglia that surround Aβ plaques. Gas6, the primary ligand for Axl, promotes phagocytosis and suppresses inflammation in peripheral immune cells.MethodTo test the hypothesis that manipulation of the Axl‐Gas6 pathway contributes to Aβ clearance, we carried out intrahippocampal injections of an AAV‐Gas6 vector in male and female APP/PS‐1 mice at 4 or 7 months of age.ResultHippocampal overexpression of Gas6 for one or six months led to decreased Aβ plaque load when compared to the opposite hippocampus injected with a control AAV‐Gas6(delta) vector that lacks the Gla and EGF domains required for Axl phosphorylation. We are currently quantifying microglial responses in these brains as well as carrying out in vitro studies with microglia from Axl knockout mice to better determine the roles of the Gas6‐Axl signaling pathway in mediating Aβ phagocytosis and microglial inflammatory responses.ConclusionAxl activation in vivo leads to reduced Aβ plaque load. Results from this work will provide insight regarding potential mechanisms that may be harnessed to reduce AD‐related pathology.