bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep duration and its association with cognition vary with rurality in older veterans
Authors: Silbert Lisa C , Wall Rachel C , Beattie Zachary , Dodge Hiroko H , Mattek Nora , Riley Thomas , Lim Miranda , Kaye Jeffrey 
Published: December 2020

AbstractBackgroundSleep duration is associated with cognitive health in older individuals and is increasingly recognized as an important modifiable factor related to dementia risk. Sleep and its relationship with cognitive function is understudied in rural U.S. Veterans, who are under‐represented in clinical research aging studies.MethodParticipants (age > 57) were enrolled as part of Collaborative Aging Research using Technology (CART), a multi‐site study examining the feasibility of unobtrusive remote sensing and monitoring of physical, cognitive, behavioral, physiological, and health‐related activities. The VA cohort consists of volunteers living in largely rural communities in the Pacific Northwest, self‐identified as being a Veteran, and included their cohabitant, if applicable. Nightly hours of sleep were estimated using a wrist worn device and baseline one month averages were compared with rural status and cognitive function.Result114 nondemented participants from 67 homes underwent neuropsychological testing and passive monitoring of daily activities (55% male, age 70.7, MOCA 23.4). 70% resided in a rural area, defined as having a rural‐urban commuting area (RUCA) score of 4 or higher (30% urban, 28% large‐rural, 34% small‐isolated‐rural). Participants with 7+ days of recorded sleep measured within a one‐month period near baseline cognitive assessments were included in the analysis (n = 99). Mean hours of sleep obtained over an average of 24.4 days was 7.8 hours (SD 1.7). Participants living in urban areas slept less (7.3 hrs) than those living in large‐rural (8.3 hrs) but not small‐isolated rural areas (7.6 hrs)(p<0.05). Poorer executive function and global cognition were related to decreased sleep duration in Veterans living in small‐isolated and large rural areas, respectively.ConclusionIn a cohort comprised of mostly rural Veteran’s and their spouses, living just outside of an urban area was associated with longer sleep duration. However, this relationship did not exist in Veterans living in smaller rural centers. Sleep duration was associated with poorer cognition in rural, not urban, Veterans. Passive, in‐home monitoring can provide objective measures of sleep activity that may serve as a sensitive index of dementia risk and as a tool to investigate sleep dysfunction and its relationship with cognitive health in older rural Veterans.
Polygenic hazard scores in superagers: Supergenes or superresilience?
Authors: Spencer Barbara E. , Banks Sarah Jane , Dale Anders M. , Brewer James B. , Makowski‐Woidan Beth , Weintraub Sandra , Mesulam Marsel , Geula Changiz , Rogalski Emily J. 
Published: December 2020

AbstractBackgroundUnusually successful cognitive aging (e.g. SuperAging) may reflect underlying resistance to age‐associated cognitive decline and the neuropathologic markers of Alzheimer’s disease (AD). However, it is unknown whether these individuals vary in their genetic protection from AD relative to other clinically normal elderly individuals.MethodThe Northwestern SuperAgers cohort (n=41) was limited to clinically normal individuals who were at least 80 years old but performed at or above normative values for average 50 to 65‐year‐olds on delayed recall of the Rey Auditory Verbal Learning Test and within one standard deviation of the average normative range for their age, or better, on non‐episodic memory tests including the 30‐item Boston Naming Test, Trail Making Test Part‐B and Category Fluency Test (Animals). The UC San Diego (UCSD) Shiley Marcos Alzheimer’s Disease Research Center and Alzheimer’s Disease Neuroimaging Initiative (ADNI) comparison cohorts (n=17 and 46, respectively) included all clinically normal individuals with available genetic data who were at least 80 years old but did not meet the criteria for SuperAgers outlined above. Polygenic hazard scores (PHS) were downloaded from ADNI and calculated for each participant as described (Desikan et al., 2017) for the Northwestern and UCSD cohorts. Briefly, the PHS combines an individual’s genotype for 31 AD‐associated SNPs in addition to APOE.ResultAll three cohorts were similar in age (range: 80‐101) and years of education (range: 12‐20). However, there were significantly more women in the Northwestern SuperAgers cohort (p < 0.001). The mean PHS in each cohort was negative, indicating that these individuals had less than average population risk for AD. However, there were no significant differences in PHS between cohorts.ConclusionAs a group, SuperAgers did not have lower polygenic risk for AD than clinically normal elderly individuals, suggesting determinants of superior memory performance in older age cannot be solely explained by having unusually low risk for AD as assessed by common genetic variants. Given the sex differences in these cohorts, future work should consider whether sex‐specific polygenic risk for AD contributes to the superior memory performance of SuperAgers.
Does feeding route affect advanced dementia patients’ caregiver burden?
Authors: Cintra Marco Túlio , Bicalho Maria Aparecida , Torres Henrique Gama , Rezende Nilton Alves 
Published: December 2020

AbstractBackgroundIndication for alternative feeding route (enteral nutrition ‐ EN) in elderly patients with advanced dementia remains controversial, especially when considering caregiver burden. The objective of this work was to evaluate caregiver burden of patients with advanced dementia with moderate to severe oropharyngeal dysphagia.MethodA cohort of 67 patients with advanced dementia, 31 on EN and 36 on oral feeding (OF), was followed for a minimum period of 6 months. The Zarit Caregiver Overload Scale was applied to caregivers on admission (D0) and 90 (D90) and 180 days (D180) after recruitment. T student test for paired samples, T student test for independent samples, linear regression logistics, Pearson correlation coefficient and multivariate analysis were employed to compare samples and to disclose independent variables related to caregiver burden. SPSS 19.0 and Stata10.0 were employed.ResultSociodemographic and clinical variables were similar between the groups. Analyzing overall sample showed caregiver burden reduction from 28.72 (D0) to 25.95 (D90) and 22.89 (D180) points of Zarit Scale, with a p‐value of 0.001 between D0 and D180 and, p=0.020 between D90 and D180. In OF group, the overload was reduced from 30 to 26.79 after 90 days (p = 0.134) and to 24.29 after 180 days (p = 0.002). Statistical significance was also observed between D90 and D180 (p = 0.029). Overload reduced from 27.04 to 23.82 from D0 to D90 and to 18.71 on D180 in EN group, without reaching statistical significance. There were no statistical differences between OF and EN groups in any time. Deaths reduced importantly sample size in EN group (n = 11, D90 and n = 7, D180). After logistic regression analysis, inverse association between Zarit Scale on D0 and family income was observed, at the limit of statistical significance (p = 0.048 and r2 = 0.048).ConclusionThere were no difference between OF and EN groups in overall caregiver burden along six months of follow up. However, significant reduction was observed in caregiver overload in OF group after 90 and 180 days of follow‐up. Also, there may be an inverse association between income and overload at recruitment.
Non‐demented elderly Latinos structurally and demographically matched to non‐Latino whites perform worse on visuo‐executive cognitive tests
Authors: Smirnov Denis S. , Galasko Doug R. , Brewer James B. , Edland Steven D. , Salmon David P. 
Published: December 2020

AbstractBackgroundPrevious work has shown that Latinos show a weaker relationship between cortical thickness and cognition in non‐demented elderly, potentially due to non‐neurodegenerative contributions. Here we examine if demographically and structurally matched Latino and Non‐Latino elderly differ in their cognitive performance and vascular risk.MethodsBoth Latino and Non‐Latino White (NLW) elderly non‐demented participants underwent structural MRI and cognitive assessment at the Shiley‐Marcos UCSD ADRC. To examine the impact of being Latino on cognitive performance when matched structurally, we took a causal inference approach by propensity score matching Latino participants in a 1:3 ratio to NLW participants on age, sex, education, and bilateral cortical thicknesses from 12 regions affected by AD (“signature”): entorhinal, parahippocampal, inferior parietal, pars opercularis, orbitalis, and triangularis, inferior temporal, temporal pole, precuneus, supramarginal, superior parietal, and superior frontal. The sample Average Treatment effects on the Treated (ATT, i.e. the causal effect of being Latino) was calculated using simulation, adjusting for the same demographics and average thickness of the “signature” regions. A 7‐point vascular risk scale was generated from history of hypertension, hypercholesterolemia, TIA/stroke, diabetes, atrial fibrillation, cardiovascular disease, and current smoking status.ResultsThe 26 Latino participants did not differ from their 78 demographically and structurally matched NLW participants on age, education, MMSE, functional impairment (POD), or cortical thickness is any of the selected regions (Table 1). However, Latino participants were more likely to have cardiovascular disease (p=0.047), and averaged 0.5 points higher on the vascular risk scale (p=0.027). The ATT of Latino on cognitive performance (Table 2) was significant for Visual Reproduction Copy [95% CI: ‐.87, ‐.31], Wisconsin Card Sorting Test categories [‐.65, ‐.13] and perseverative errors [.29, 1.28], Digit Span [‐4.00, ‐2.25], Block Design [‐9.02, ‐4.55], and Trails A [2.52, 7.72] and B [23.4, 40.6].ConclusionsDemographically and structurally matched non‐demented Latino and Non‐Latino participants exhibited comparable general cognitive performance, as well as performance on tests of memory and language. However, Latino participants had significantly lower scores on a broad range of visuospatial and executive tests. We hypothesize that this may be related to the increased vascular risk in the matched Latino group.
Hippocampal volume loss is associated with PET amyloid deposition in nondemented elderly individuals
Authors: Sathishkumar Mithra , Larson Myra S. , Taylor Lisa , Keator David , Hollearn Martina K. , Miranda Blake A. , Tustison Nick , McMillan Liv , Gillen Daniel L. , Yassa Michael A. 
Published: December 2020

AbstractBackgroundAmyloid‐beta (Aβ) plaques are among the hallmark pathologies of Alzheimer’s disease (AD) and could potentially influence the aggregation of tau pathology, which is associated with neurodegeneration in AD. Prior work has demonstrated that left hippocampal atrophy is present in both Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, these relationships are not clear in preclinical AD (i.e. those with Aβ biomarkers but no clinical impairment). This study assesses the relationship between Aβ pathology and hippocampal volume in nondemented older adults without clinical impairment.MethodData from 54 adults (60‐85 years of age, 41 female) enrolled in the Biomarker Exploration for Aging, Cognition, and Neurodegeneration (BEACoN) study were included in this analysis. Participants underwent T1‐weighted MRI scans (MPRAGE) and PET amyloid scans with F18‐florbetapir (AV‐45) at the University of California, Irvine. Aβ status (+ or ‐) was determined by the composite score defined by Jack et al (Alz Dem 2017). Each subject’s T1 weighted MRI image was skull stripped and run through the joint label fusion (JLF) pipeline in ANTs to obtain medial temporal lobe subregion volumes and surface area. Cortical reconstruction was performed using Freesurfer 6.0 to obtain estimated total intracranial volume (ICV). All scans were then subjected to visual QC to ensure high quality segmentations. Of the sample of 54, 39 (29F) were Aβ‐ and 15 (12F) were Aβ+. We used two multiple regressions to determine if Aβ status was associated with left hippocampal volume. The first treated Aβ status as a binary variable and the second used the continuous SUVR measure in the AD composite region. Both models accounted for the effect of age and gender.ResultWe found a significant association between left hippocampal volume and Aβ status, which remained significant after adjusting for age and gender. The result was further corroborated by using the continuous SUVR measures.ConclusionOur results suggest that the association between amyloid deposition and hippocampal atrophy may begin years before the onset of Alzheimer’s disease and can be detected even in nondemented older adults. Future work is needed to examine whether these relationships change longitudinally.
Alzheimer’s disease: Blood serum circulating microRNAs as diagnostic biomarkers
Authors: Giles Abdul‐Mannaan 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common age‐related dementia. One of its biggest challenges is identifying signature molecular expressions that would detect it before the clinical symptoms manifest. With advances in technology related to next generation sequencing (NGS) of microRNAs, several avenues are being explored that may enable the identification of a unique diagnostic marker for early‐stage ADMethodThe main goal was to investigate the expression of a select group of miRNAs circulating in blood serum of AD patients in search of diagnostic markers for Alzheimer’s disease. Two select blood plasma miRNAs were profiled using miRCURY LNA miRNA qPCR serum array on five AD samples.ResultResults showed that the two target sequences hsa‐miR‐181b‐3p and hsa‐miR‐21p were present in the AD samples with an increased adjusted expression (miR‐181b Ct = 29 and miR‐21p Ct = 27 respectively) compared to normal controls (xCt = 31).ConclusionThese outcomes suggest that aberrant expression of plasma miRNA has potential to be used to assess AD and that next generation sequencing technologies can be used as a viable tool for enhancing AD diagnosis.
Blood‐brain barrier permeability measured by 7α‐hydroxy‐3‐oxo‐4‐cholestenoic acid in CSF associates with Alzheimer’s pathology biomarkers in cerebrospinal fluid
Authors: Heston Margo B. , Vogt Nicholas M. , Kohli Akshay , Sun Yi , Kerby Robert L. , Carlsson Cynthia M. , Engelman Corinne D. , Johnson Sterling C. , Asthana Sanjay , Ulland Tyler , Blennow Kaj , Zetterberg Henrik , Rey Federico E. , Bendlin Barbara B. 
Published: December 2020

AbstractBackgroundThe intestinal microbiota may modulate Alzheimer’s disease (AD), however the mechanisms by which it impacts the brain remain unknown. A leading proposal suggests that altered gut permeability promotes systemic inflammation, which may impact blood‐brain barrier (BBB) and exacerbate AD pathology. To test this hypothesis, we performed analyses on levels of 7α‐hydroxy‐3‐oxo‐4‐cholestenoic acid (7‐HOCA), a potential BBB permeability marker, calprotectin in stool, a gastrointestinal inflammation marker, and cerebrospinal fluid biomarkers of AD pathology. We tested for differences in BBB by cognitive diagnosis, associations with AD biomarkers in CSF, and potential mediation by calprotectin.MethodCSF was collected via lumbar puncture from participants in the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center [CU (N=334), AD mild cognitive impairment (MCI) (N=35), AD dementia (N=40)]. Stool samples from 25 of these participants [CU (N=16), AD (N=9)] were additionally analyzed for calprotectin levels (ELISA, Eagle Biosciences). 7‐HOCA relative abundance in CSF and plasma was measured via Metabolon’s UHPLC/MS metabolomics platform. CSF biomarkers included Aβ42/Aβ40, NfL, pTau, tTau, YKL‐40 and neurogranin. Multiple linear regressions (R) were performed across 7‐HOCA, calprotectin and AD biomarkers controlling for age, sex and APOE ε4 carrier status.Result7‐HOCA levels in CSF were significantly increased in AD compared with CU participants (Figure 1). pTau/Aβ42 was significantly negatively associated with 7‐HOCA (Figure 2), while pTau, tTau, YKL‐40, NfL, and neurogranin were significantly positively associated with 7‐HOCA levels. Aβ42/Aβ40 was not associated with 7‐HOCA. Elevated calprotectin associated with CSF amyloid positivity (Figure 3), but due to small sample size this did not meet statistical significance. No significant associations were found with plasma 7‐HOCA, or with calprotectin moderating the biomarker/7‐HOCA relationships.Conclusion7‐HOCA is elevated in AD dementia, and is associated with markers of AD, neurodegeneration, and glia activation measured in CSF, potentially suggesting altered BBB in AD. While model coefficients suggest relationships between AD biomarkers and the calprotectin*7‐HOCA interaction term, the results were not significant, likely due to the small N for calprotectin analyses. Additional analyses are needed to determine whether the effects of gut microbiota on brain may be mediated by altered intestinal and BBB permeability.
Lipid metabolism dysfunction in progranulin mutation carriers: Unbiased metabolomics reveals strong relationship to clinical status in FTLD
Authors: Vandevrede Lawren , Rojas Julio C. , Wang Ping , Heuer Hilary W. , Karydas Anna M. , Ljubenkov Peter A. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. ,   ARTFL and LEFFTDS Consortia Investigators
Published: December 2020

AbstractBackgroundHeterozygous progranulin (GRN) mutations are an important cause of familial Frontotemporal Lobar Degeneration (f‐FTLD) associated with TDP‐43 pathology. The cellular role of progranulin remains unclear, but alterations in lipid metabolism and lysosomal function have been suggested. Better understanding the pathophysiology of progranulin deficiency is critical as several clinical trials are underway in this population, and fluid biomarkers are urgently needed to assess pharmacodynamic effects. Therefore, we conducted an unbiased metabolomic analysis in GRN mutation carriers and family member controls, and identified at least two classes of lipids altered in symptomatic GRN carriers.MethodsMatched plasma and CSF samples were obtained from GRN mutation carriers (46 plasma, 36 CSF) and age‐matched blood relatives (36 plasma, 18 CSF). Untargeted metabolite detection was conducted via LC‐MS/MS in both plasma (1389 compounds) and CSF (508 compounds) by Metabolon. To identify important compounds in differentiating these groups, we conducted an unbiased analysis between family controls, asymptomatic carriers, and symptomatic carriers using univariate one‐way ANOVA with post‐hoc Fisher’s LSD corrected for false discovery rate (FDR) and partial least squares ‐ discriminant analysis (PLS‐DA, Metaboanalyst). For compounds identified by this unbiased approach, correlation with measures of disease severity was analyzed via linear regression, controlling for age and gender.ResultsIn plasma, 22 compounds were identified as significant in discriminating between groups via ANOVA (FDR<0.05), and 17/22 were also identified by PLS‐DA (VIP>2.4). Of these, 21/22 compounds were lipids; 11 were sphingomyelins. Comparatively, in the relatively lipid‐poor CSF samples, 6/15 compounds identified by PLS‐DA (VIP>2.0) were phosphatidylcholines. Pathway impact analysis revealed a large impact from the GRN mutation on sphingolipids in plasma and glycerophospholipids in CSF. In secondary analyses, sphingomyelins were elevated in plasma from symptomatic carriers, while phosphatidylcholines were decreased in CSF. Secondary analyses showed these compounds were correlated with clinical measures of disease severity, including MoCA and CDR+NACC‐FTLD.ConclusionIncreased plasma concentration of sphingomyelin and decreased CSF phosphatidylcholines are both associated with worse clinical status in FTLD‐GRN. These findings suggest that impaired lipid metabolism could play a pathogenic role in FTLD‐GRN. Targeted lipidomic measures in plasma and CSF may potentially reveal useful clinical trial biomarkers.
Quantifying acute tau inoculations in living rats using PET
Authors: Kunach Peter 
Published: December 2020

AbstractBackgroundMonitoring tau propagation in the living brain has important pathophysiological and therapeutic implications. Previous studies assessing tau propagation relied on cross‐sectional immunohistochemical techniques in post‐mortem tissue, as such little is known regarding the behaviour of tau preparations in living systems. As tau imaging agents are dependent on tau conformations, we aim to determine the tau species amenable to in vivo imaging. As such, the goal of this work is to examine the binding properties of [18F]MK‐6240, a second‐generation tau imaging agent in different tau preparations.MethodSeven Fisher 344 rats (15± 0.25 months) were used. All animal had a baseline scan with [18F]MK6240 before the stereotaxic tau injections. We tested various recombinant human tau PFFs and patient derived AD‐tau following gel extraction or serial filtration extraction. All tau preparations were stereotaxically injected in the dorsal hippocampus (DV: ‐3.5; AP: ‐3.5; ML:‐2). All recombinant tau PFFs had an injection volume of 2uL and concentration of 4ug/uL, whereas AD‐tau had an injection volume of 2uL and a concentration of 0.4 ug/uL. Structural MRI were conducted following surgery to determine the final position of the injection site. All animals underwent to a 1 hour dynamic acquisition PET with [18F]MK6240. The non‐displaceable binding potential (BPND) images were generated using cerebellar grey as a reference region based on Simplified Reference Tissue Method (SRTM). The comparison of the images was conducted using z‐scores.ResultWe injected a total of 7 rats with varying tau extracts. We found that the hemispheres injected with human tau extracts from both filtration and gel electrophoresis preparation method showed positive BPnd signals versus hemispheres with control injections. Both recombinant human tau PFF’s lacking FTD‐mutations show positive [18F]MK‐6240. The entire procedure was well tolerated by the animals.ConclusionThese results reveal that PET [18F]MK‐6240 constitutes a promising method for quantification of tau seeding and propagation in the rat brain. Not all tau preparations provide binding sites for [18F]MK6240 binding. Future longitudinal studies will reveal whether these techniques will be able to capture tau propagation.