bluuebunny/crossref_metadata_2025_split huggingface dataset:
Why does ARIA‐E appear bright? A quantitative model linking brain tissue composition and T2 FLAIR hyperintensities
Authors: Aldea Roxana , Grimm Hans Peter , Gieschke Ronald , Hofmann Carsten , Klein Gregory , Kunnecke Basil , Piazza Fabrizio , Carare Roxana O , Mazer Norman A 
Published: December 2020

AbstractBackgroundAmyloid related imaging abnormalities (ARIA) detected by magnetic resonance imaging (MRI) are associated with a class of therapeutic anti‐amyloid‐β antibodies under investigation in Alzheimer’s disease. ARIA‐E, manifested as bright signals on the T2 fluid attenuated inversion recovery (FLAIR) sequence, are suggestive of parenchymal vasogenic edema and/or sulcal effusions, although, solid experimental support is still missing [1]. By employing a novel voxel‐based model of the MRI signal, we test whether the extravasation of fluid and plasma proteins in the brain tissue and/or sulcal spaces can indeed explain the T2 FLAIR hyperintensities characteristic for ARIA‐E.MethodThe modelled MRI voxel consists of myelin (my), intracellular (ic) and extracellular (ec) compartments (Figure 1). The material properties and MRI parameters (T1 and T2 relaxation times) of the physiological system come from experiments on protein solutions and human brain (Table 1). The movement of water molecules between the ic and ec compartments is assumed to be fast and to generate a well‐mixed intra/extra‐cellular (iec) compartment. The net T2 FLAIR signal within the voxel is assumed to result from the water in the my and iec compartments undergoing slow exchange and having independent magnetic relaxation. We assess how expanding the ec space with a protein‐rich fluid affects the T1 and T2 relaxation times of the ec and iec compartments and the total FLAIR signal within the voxel.ResultOur model predicts that a two‐fold enlargement of the ec space, corresponding to a 12% increase in water volume, can lead to a substantial parenchymal hyperintensity on T2 FLAIR. The presence of a protein‐rich fluid, e.g. plasma, in the ec space cannot yield parenchymal hyperintensities in the absence of ec expansion. Conversely, replacing the cerebrospinal fluid from the sulci (normally appearing dark on T2 FLAIR) with protein‐rich fluid results in a signal comparable to normal grey matter and the apparent loss of sulci (Figure 2).ConclusionBy linking brain tissue composition to FLAIR signal changes, our model could help unravel the pathophysiological mechanisms of ARIA‐E and, therefore, provide a useful tool for testing other potential mechanisms underpinning brain MRI abnormalities. Reference: (1) van Dyck, Biological Psychiatry, 2018, 83(4):311‐319.
Single nuclei RNA‐seq data analysis identifies glial cell lineages associated with Alzheimer’s disease severity
Authors: Elyanow Rebecca , Green Kevin J. , Greenwood Anna K. , Prater Katherine E. , Melief Erica J. , Valdmanis Paul , Blue Elizabeth E. , Keene C. Dirk , Crane Paul K. , Young Jessica E. , Garden Gwenn A. , Jayadev Suman , Logsdon Benjamin A. 
Published: December 2020

AbstractBackgroundSingle nucleus RNA sequencing (snRNA‐seq) has the potential to improve our understanding of the cellular‐specific drivers of sporadic Alzheimer’s disease. In this study we re‐analyze published snRNA‐seq data from post‐mortem dorsolateral prefrontal cortex tissue from 48 participants in the Religious Order Study and Memory and Aging Project (ROS/MAP) cohorts (Mathys et al. 2019) and snRNA‐seq data from prefrontal cortex tissue from 9 participants across the Adult Changes in Thought (ACT), University of Washington Alzheimer’s Disease Research Center (UW‐ADRC), and Seattle Longitudinal Study (SLS) cohorts.MethodAll snRNA‐seq data were normalized using scran, with normalized counts pre‐processed in Monocle 3. Pseudotime lineages were learned separately for male and female patients for each cell subtype with Monocle3. Genes with non‐zero counts in fewer than 10 cells in a subtype were discarded.ResultWe reidentified the ROS/MAP disease‐associated microglia subtype (Mic1) from Mathys et al. 2019 in the ACT, UW‐ADRC, and SLS data as determined by Fisher’s exact test overlap of subtype specific gene expression markers (p.adjusted<10−16). Furthermore, we identify a trajectory of cellular state (pseudotime) within the Mic1 population that is disease associated (p.adjusted ≤ 3.4 × 10−11 in females, and p.adjusted ≤ 4.8 × 10−4 in males) in the Mathys et al. data. In female samples in both studies we observed that APOE expression has a positive association with Mic1 pseudotime, which we do not see in males. In males we see MEF2C expression was negatively associated with Mic1 pseudotime. Lastly, we see both activation of similar Mic1 pseudotime expression patterns in a subpopulation of oligodendroglial cells, as well as a loss of oligodendroglial cells in diseased patients.ConclusionWe provide increasing evidence implicating a specific microglial subpopulation in the etiology of Alzheimer’s disease. Furthermore, we see that this population has heterogeneity in expression of key Alzheimer’s disease risk genes as a function of sex, and that we can define genes that are specific to this microglial subtype lineage for further functional investigation. Finally, we also see evidence of a similar disease‐associated expression signature in oligodendroglial cells, suggesting potentially an interaction between the disease associated microglia populations and oligodendrocytes in diseased patients that warrants further functional investigation.
Can motion‐based technology impact balance, movement confidence, and cognitive function among people with cognitive impairment?
Authors: Dove Erica , Wang Rosalie , Zabjek Karl , Astell Arlene J. 
Published: December 2020

AbstractBackgroundBalance, movement confidence, and cognitive function are related to falls among people with cognitive impairment (PwCI; e.g. dementia). Motion‐based technologies (MBT; e.g. Xbox Kinect) are increasingly being explored to encourage exercise participation among PwCI, which can prevent falls. This study is examing the impacts of a group MBT intervention on balance, movement confidence, and cognitive function among PwCI.MethodsTwenty‐four PwCI played Xbox Kinect bowling twice weekly for ten weeks at four adult day programs. The Mini Balance Evaluation Systems Test (Mini‐BEST) and the Montreal Cognitive Assessment (MoCA) were completed pre‐ and post‐intervention. Video recordings were taken during weeks one, five, and ten used to capture behavioural indicators of movement confidence (e.g. fluency of motion). Quantitative data collected through the Mini‐BEST and MoCA are being compared from pre‐ to post‐test using paired t‐tests. An ANCOVA is also being performed to account for covariates (e.g. number of intervention sessions attended). Count and percentage data are being extracted from coded video recordings to examine movement confidence.ResultsThis study will answer questions regarding the potential of a group MBT intervention to impact balance, movement confidence, and cognitive function among PwCI. This could assess the feasibility and potential benefits of using MBT to deliver exercise interventions to PwCI. Finally, this work can be used as the basis for developing specific software and future exercise programs using MBT for PwCI.ConclusionThe findings will be used to inform future MBT applications to deliver exercise to PwCI.
Performance and intrusion errors on challenging cognitive assessments associate with subjective cognitive decline
Authors: Joyce Jillian L. , Chapman Silvia , Barker Megan S. , Rizer Sandra , Sunderaraman Preeti , Charles Kreisl William , Cosentino Stephanie 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) in ostensibly cognitively normal older adults has been proposed to reflect preclinical Alzheimer’s disease (AD). Yet traditional neuropsychological tests have inconsistently linked SCD and cognitive performance, possibly reflecting the lack of sensitivity and specificity in such tests to capture subtle cognitive changes. Indeed, novel cognitive tests as well as intrusion errors appear to be more closely associated with preclinical AD biomarkers. However, there is limited investigation into the association of SCD with these cognitive outcomes. This study examines SCD in relation to the main outcomes and intrusion errors on two novel challenging cognitive tasks, and a traditional neuropsychological test.Method94 healthy older adults with a mean age of 73 years (SD=7.36), and education of 17 years (SD=2.34) were recruited for this study. Participants completed three SCD questionnaires regarding common cognitive difficulties in memory, language, attention and executive functioning. A single factor score was derived as main outcome for SCD. Cognitive assessment included the Loewenstein‐Acevedo Scale for Semantic Interference and Learning (LASSI‐L), the Face‐Name Associative Memory Exam (FNAME) task, and the Selective Reminding Test (SRT). Main outcomes for each measure included: SRT (total and delayed recall and intrusion errors); LASSI‐L (recovery from semantic interference, percentage of intrusions errors, total semantically related intrusions (SRI) and competing item intrusions (CII)); FNAME (total names recalled, SRI and CII). Demographically adjusted linear regressions were conducted to examine the unique contribution of performance and intrusion errors on each measure to SCD.ResultBoth FNAME names recall (β=‐.24, p=.027) and SRI (β=.25, p=.015) were independently associated with SCD, while overall intrusions and CII were not (p>.05). The LASSI‐L overall intrusions (β=‐ .30, p=.009) and CII (β=‐ .29, p=.014) were also associated with SCD, while SRI and recovery from semantic interference were not. (p>.05). No SRT outcomes were associated with SCD (p>.05)ConclusionSCD appears to capture subtle changes on sensitive cognitive measures proposed to be indicative of preclinical AD. Results support the use of both main outcomes and intrusion errors on these cognitive tests, as they may each reveal sensitive information regarding various mechanisms that can breakdown in early AD.
Genome‐wide interaction study of smoking in Alzheimer’s disease
Authors: Moore Mackenzie R. , Chung Jaeyoon , Rosenthaler Max , Uretsky Madeline , Abdolmohammadi Bobak , Raghavan Neha S. , Farrell John , Bennett David A. , Crane Paul K. , Kamboh M. Ilyas , Kukull Walter A. , Larson Eric B , Haines Jonathan L. , Pericak‐Vance Margaret A , Schellenberg Gerard D , Mayeux Richard , Lunetta Kathryn L , Farrer Lindsay A. , Mez Jesse ,   Alzheimer’s Disease Genetic Consortium
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) have identified approximately 40 risk loci associated with Alzheimer’s disease (AD). However, only a fraction of heritability has been explained. In large meta‐analysis, smoking was associated with AD dementia. In this study, we sought to identify interactions between smoking and single‐nucleotide polymorphisms (SNPs) to further characterize AD genetic architecture.MethodWe used a subset of datasets of individuals of European ancestry from the Alzheimer’s Disease Genetic Consortium (ADGC) that had smoking information available from parent studies. The presence of any past or current smoking habit was considered to be positive smoking exposure. In each dataset, we ran a genome‐wide case‐control analysis including SNP and smoking main terms, and a SNP‐smoking interaction term. Models were adjusted for age, sex, and principal components of population substructure. Results from each dataset were meta‐analyzed using the inverse variance method. Pathway analysis of top SNPs was run using Ingenuity.ResultThe sample included 6,916 total individuals, including 2,862 AD cases and 4,054 controls. Although no interaction terms reached genome‐wide significance, there were two suggestive loci: top SNP rs3734416 [minor (C) allele frequency (MAF) = 0.27; interaction P = 7.2 × 10−6; OR for C allele in smokers = 1.23; OR for C allele in non‐smokers = 0.86] on chromosome 6 within the gene MTHFD1L and 95kb downstream of PLEKHG1, and top SNP rs693951 [MAF (G) = 0.27; interaction P = 1.3 × 10−6; OR for major A allele in smokers = 1.31; OR for A allele in non‐smokers = 0.83] on chromosome 8, 70kb upstream of ANGPT1. Pathway analysis implicated cellular development, cellular growth and proliferation and nervous system development and function. MTHFD1L has been implicated in candidate gene studies of AD and PLEKHG1 has been implicated in a GWAS of white matter hyperintensities. ANGPT1 has been implicated in recovery after ischemic stroke in candidate gene, transcriptomic and blood‐based biomarker studies.ConclusionWe found suggestive evidence of a smoking‐SNP interaction associated with AD risk at 2 loci previously linked with AD and cerebrovascular disease, but that were not identified in the largest AD GWAS to date. Expansion of the sample and replication are underway.
A study of prevalence and factors related to cognitive impairment in Thai patients with neuromyelitis optica
Authors: Rattanabannakit Chatchawan , Lerttanatum Chompoonuch , Maethasith Inthiporn , Siritho Sasithorn , Jitpapaikulsarn Jiraporn , Prayoonwiwat Naraporn , Senanarong Vorapun 
Published: December 2020

AbstractBackgroundNeuromyelitis Optica (NMO) is a demyelinating disease caused by an autoimmune process that attacks the central nervous system resulting in a neurological deficit. Previous studies showed cognitive problems in these patients, especially the decline in processing speed, episodic memory, executive function, and attention. We aimed to study the prevalence and the factors related to cognitive impairment in Thai patients with NMO.MethodWe recruited 83 participants diagnosed with NMO by the 2015 international consensus diagnostic criteria for NMO spectrum disorder who visited the Demyelinating Disease Clinic at Siriraj Hospital. Participants with the last clinical relapse within 3 months or those who could not perform cognitive tests due to disability were excluded. Cognitive functions were assessed by using the Montreal Cognitive Assessment – Thai version (MoCA‐T) and Frontal Assessment Battery (FAB). The subjective reports of any cognitive problem by interviewing participants and their informants were also collected. Demographic data, cognitive performance, and factors related to the MoCA‐T score were analyzed.ResultThe mean MoCA‐T score in patients with NMO was 22.96 ± 3.82, and the mean FAB score was 15.27 ± 2.47. The majority (54%) of them had cognitive impairment according to the cut‐off of the MoCA‐T score of less than 25. Participants with cognitive impairment had significantly less education than those without cognitive impairment (9.9 4.3 and 14.6 3.6 years, p < 0.001), and they used more time to complete the MoCA‐T (p < 0.001). The disease severity evaluated by the Expanded Disability Severity Scale was associated with the MoCA‐T score (r = ‐0.29, p = 0.008). Age, the annual relapse rate in the first five years, duration of disease, and Aquaporin‐4 antibody status were not associated with cognitive impairment (all p > 0.5). Interestingly, the informant‐report of cognitive decline in NMO patients was associated with the less MoCA‐T performance (p = 0.032), but not the self‐report (p = 0.397).ConclusionMost of the Thai patients with NMO had cognitive impairment, which related to education, disease severity, and also the perception of their relatives. Future studies that included more comprehensive neuropsychological evaluations and neuroimaging findings are needed in these patients.
Defining the role of gut microbiota‐derived ketamine metabolites in Alzheimer’s disease
Authors: Pasinetti Giulio Maria , Naughton Sean X. , Trageser Kyle J. , Harary Joyce M. , Westfall Susan 
Published: December 2020

AbstractBackgroundKetamine, typically used for providing pain relief and sedation prior to surgical procedures, has recently been recognized as a potential therapy for disorders rooted in neuroinflammation such as major depression. Ketamine undergoes extensive metabolism and characterizing these metabolites is essential to understand the therapeutic efficacy and long‐term effects of ketamine treatment for neuroinflammation. Further, specific enantiomers of ketamine have been shown to specifically alter the composition of the gut microbiota, which through gut‐brain‐axis mechanisms, may contribute to its anti‐inflammatory activity. The objective of this study is to characterize the impact of the gut microbiota on ketamine metabolism and using these metabolites understand how ketamine can be used as a therapeutic for neuroinflammation associated with Alzheimer’s disease (AD).MethodUsing an in vitro model of the human gastrointestinal tract, EBIOME we are exploring the impact of ketamine on the human microbiome with metagenomic quantification of gut microbiome species and quantification of ketamine metabolites with UPLC‐MS/MS technology platforms. Ketamine is known to undergo extensive metabolism by liver P450 enzymes, which will interact with the gut microbiome derived metabolites. Hence, following validation in vitro, in ongoing studies ketamine will be chronically dosed into wildtype mice to understand how the gut microbiota‐derived metabolites affect the known liver‐derived secondary metabolites including norketamine and its hydroxylated isomers and dehydrogenated forms.ResultWe have evidence in rodents, that ketamine amplifies Lactobacillus, Turicibacter and Sarcina spp. while reducing populations of the opportunistic pathogens Mucispirillim and Ruminococcus indicating that there is a species‐dependent metabolism of ketamine. Bioavailability and acute over chronic pharmacokinetics of these metabolites will be determined in the gut, blood and brain to understand how the gut‐liver metabolic interactions affect chronic ketamine dosing towards understanding the long‐term safety of ketamine.ConclusionWith an understanding of ketamine metabolism, ketamine chronically dosed into 5xFAD AD mouse models we will understand the brain‐bioavailable ketamine metabolites on neuroinflammatory pathophysiologies of AD. Ultimately these studies will help to asses microglia inflammatory activation and Alzheimer’ disease neuropathology.
Beers criteria medications administered intraoperatively to older surgical patients with cognitive impairment
Authors: Schenning Katie J , Navales Andres Tirado , Tekkali Praveen , Quinn Joseph F 
Published: December 2020

AbstractBackgroundThe American Geriatrics Society maintains a list of drugs that are not recommended for geriatric patients with dementia or cognitive impairment (i.e. Beers Criteria) due to increased risk of delirium. Several drugs from this list are commonly used in the perioperative period, including benzodiazepines and drugs with anticholinergic properties. Our objective was to determine the prevalence of potentially inappropriate medication (PIM) administration intraoperatively in geriatric surgical patients who screened positive for cognitive impairment.MethodThis was a retrospective evaluation of 2,410 older adults (at least 65 years) who presented for elective, inpatient surgery between February, 2018, and January, 2020, in a large tertiary teaching hospital. Patients were screened preoperatively for cognitive impairment using the Mini‐Cog. Mini‐Cog scores 0‐2 were considered positive for cognitive impairment. Charts were reviewed to analyze which 2019 Beers Criteria medications were administered intraoperatively by the anesthesiology team. An unpaired t‐test was performed to determine whether there was a difference in PIM administration in patients who screened positive vs negative for cognitive impairment.ResultAmong 2,410 geriatric surgical patients with a mean age of 73 years, 1,817 (75.4%) had at least one PIM administered during surgery/anesthesia. The most commonly administered medications were steroids (n=1096, 45.5%), medications with anticholinergic properties (n=930, 38.6%), and benzodiazepines (n=852, 35.4%). (Table 1) Patients who screened positive for cognitive impairment received fewer PIMs on average than patients who had a negative cognitive screening test. (mean ± SEM, 1.03±0.05 vs. 1.24±0.02 PIM, p<0.001). (Table 2)ConclusionThere is a high prevalence of PIM used in geriatric surgical patients, including patients who have screened positively for preexisting cognitive impairment.
Dementia is strongly associated with atrophy of medial temporal lobe structures even after accounting for neuropathologies
Authors: Woodworth Davis C. , Sheikh‐Bahaei Nasim , Scambray Kiana Alexis , Phelan Michael , Corrada Maria M.M. , Kawas Claudia H. , Sajjadi S. Ahmad 
Published: December 2020

AbstractBackgroundBrain atrophy is associated with various neuropathologies as well as clinical status of dementia. However, few studies have examined if dementia has an independent effect on brain atrophy. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia‐related neuropathologies.MethodWe used data from the National Alzheimer’s Coordinating Center (NACC) (09/2005‐03/2017) and identified 129 participants with suitable 3D‐T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We used the following dichotomized neuropathological variables in our analysis: Alzheimer’s disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis, gross infarcts, microinfarcts, and micro/macro hemorrhages. We used the Computational Anatomy Toolbox (CAT12) to segment the T1w scans into tissue types and generate gray matter density maps. First, we performed a voxel‐based morphometry (VBM) analysis to identify regions associated with dementia. We further explored this relationship by analyzing the volumes of the identified regions of interest (ROI). Also, to examine the association of dementia with global measures of atrophy, we assessed the relation of dementia with total gray matter, white matter, and cerebrospinal fluid. We used multiple linear regression models of density/volumes in relation to dementia while adjusting for neuropathologies, sex, age, education, years from MRI to death, and intracranial volume.ResultTable‐1 summarizes participant characteristics. VBM showed that grey matter atrophy of hippocampus and surrounding structures had the strongest association with dementia (Figure‐1). Therefore, we selected the hippocampus, amygdala, and medial temporal cortex for ROI analysis. We found strong associations with dementia for volumes of the hippocampus, amygdala, and medial temporal cortex (P<0.0001 and semi‐partial correlations≥0.25 for each, Table‐2). Dementia status accounted for more variance in atrophy in these structures (∼8%) compared with all demographic and neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%, Table‐3).ConclusionEven after accounting for the most common neuropathologies, dementia still had the strongest association with atrophy of medial temporal lobe structures. This suggests that atrophy of the hippocampus and medial temporal lobe is most related to clinical dementia as opposed to Alzheimer's disease neuropathology.