bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative ‐omics for discovery of network‐level disease biomarkers for Alzheimer’s disease
Authors: Xie Linhui , He Bing , Varathan Pradeep , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Salama Paul , Yan Jingwen 
Published: December 2021

AbstractBackgroundA large number of genetic variations have been identified to be associated with Alzheimer’s disease (AD) and related traits. But the downstream biology through which they exert effect on the development of AD remains unknown. Leveraging genomic, transcriptomic and proteomic data, and various biological networks, we proposed a modularity‐constrained logistic regression model (M‐logistic) to identify a set of functionally connected SNPs, genes and proteins related to AD.MethodThe GWAS genotype data, RNA‐Seq gene expression data and Protein expression data were obtained from the ROS/MAP Project. Detailed data processing steps can be found in AMP‐AD (https://www.synapse.org). In total, 179 subjects with full set of data were included (Table. 1). Using peptides as seed, we prefiltered the data and included 186 peptides, 743 unique genes and 822 Single‐nucleotide polymorphisms (SNPs) from upstream of their connected genes (Fig. 1). Functional interactions from REACTOME database [1] and the SNP‐gene mapping relationship were used to construct the prior network. These functional connected ‐omics features were used to classify AD patients from non‐symptomatic group, including cognitive normal and mild cognitive impairment.ResultAcross 10‐fold cross‐validation, we observed that M‐logistic largely outperforms other state‐of‐the‐art models (Table. 2). For feature selection, the proposed model identified 305 features predictive of disease status, which appeared in more than 6 folds. When mapped back to the prior network, these features formed three big sub‐networks with > 10 nodes (Fig. 2). For 20 genes in the largest sub‐network, their brain‐wide expression profile in the Allen Human Brain Atlas were found to be mostly correlated with the activation map of brain function term “vision” in Neurosynth [2] (Fig. 3).ConclusionM‐Logistic identified a set of SNPs, genes and proteins that are not only predictive of AD but also densely connected in the prior network. The trans‐omic paths in the selected sub‐networks indicates a potential pathway underlying the development of AD from SNPs to gene expression, protein expression and ultimately brain functional and structural changes. Future efforts are warranted to enable integrative analysis of multi‐omics data from decoupled subjects. [1] Fabregat et al., Nucleic acids research, 2018. [2] Yarkoni et al., Nature Method, 2011.
Dementia with Lewy bodies (DLB) with amyloid co‐pathology has a distinct CSF proteomics profile compared to pure DLB and Alzheimer disease
Authors: Vermunt Lisa , Doelkahar Brian S. , Peeters Carel F.W. , van de Beek Marleen , Visser Pieter Jelle , Tijms Betty M. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Irwin David J. , Chen‐Plotkin Alice , Lemstra Afina W. , Del Campo Marta , Teunissen Charlotte E. 
Published: December 2021

AbstractBackgroundIn dementia with Lewy bodies (DLB), amyloid co‐pathology is common and associated with an unfavorable prognosis. For targeted treatment development for DLB, we need to establish 1) whether the presence of amyloid marks co‐occurring Alzheimer disease (AD), and 2) how DLB with amyloid differs from DLB without amyloid. We employ proteomics in cerebrospinal fluid (CSF), an established method to assess biological dysregulation in vivo, for characterization of DLB with amyloid pathology.MethodWe selected individuals from the ADC and UPENN cohorts, with DLB diagnosis with abnormal amyloid based on CSF (n=65), DLB with normal amyloid (n=45), AD dementia (n=235), and cognitively healthy controls with normal amyloid (n=252, Table 1). CSF protein levels (n=810) were measured using the Olink proximity extension assay. We compared protein levels between groups using ANCOVA’s adjusted for age and sex, and FDR‐controlled p‐values. To aid identification of proteins that contribute to disease processes, we developed a neural network model prototype. We trained the model to learn simultaneously a low dimensional representation of the data and a dementia classifier. The assumption is that biologically important proteins show the strongest influence on the low network dimension, because these proteins contribute to classification and/or share information with multiple proteins.ResultThe DLB‐amyloid group showed mostly decreased CSF protein levels, in particular compared to AD dementia (68%, Table 2). Compared to DLB‐pure, DLB‐amyloid has 132 decreased and 3 increased protein levels, which were most significantly enriched for KEGG pathways: cytokine‐cytokine receptor interaction and axon guidance; and for GO‐biological terms related to positive regulation of neurogenesis, axonogenesis, and neuronal differentiation. In DLB‐amyloid, most AD‐related proteins were normal or decreased, and multiple additional proteins were specifically decreased (Figure 1) These DLB‐amyloid associated proteins were enriched for GO‐biological terms related to chemotaxis and VEGF‐A induced cell proliferation.ConclusionThe CSF proteome in DLB with amyloid pathology differed from AD dementia and DLB pure, and the changes may be linked to disturbed axonal maintenance and growth. This data indicate that amyloid pathology in DLB is not an independent co‐pathology. Complementary to pathology studies, we have started to disentangle mechanisms of mixed pathology in vivo.
Structural correlates of moral emotions in patients with behavioral variant frontotemporal dementia
Authors: Chonchol Andrea Slachevsky , Trujillo Catalina , Forno Gonzalo , Bleier Cristina , Lillo Patricia , de Souza Leonardo Cruz , Baez Sandra 
Published: December 2021

AbstractBackgroundSocial cognition impairments have been extensively described in patients with behavioral variant frontotemporal dementia (bvFTD). Moral emotions have recently emerged as a potentially sensitive domain to characterize and discriminate bvFTD patients from other types of dementia. Here, we examined the usefulness of moral emotions measures to characterize and discriminate bvFTD from Alzheimer’s disease (AD) patients, and their structural brain correlates in both groups.MethodIn this multicenter (Chile‐Colombia) study, 31 bvFTD, 30 AD patients, and 37 healthy controls –matched by age, sex, and educational level– completed an adapted version of the Moral Sentiments Association Task (MSAT) consisting of 29 text‐based scenarios evoking moral (guilt, pity, embarrassment, and indignation) and basic (fear and disgust) emotions. After reading each scenario, participants selected the emotion they would feel in that situation and rated their elicited intensity and disturbance levels. General cognitive (MoCA/ACE‐III) and executive (IFS) measures were also included. Additionally, we performed VBM analysis in a subsample (15 bvFTD, 20 AD, 17 controls) to study the association between grey matter volumes and moral emotions processingResultAfter controlling for cognitive and executive skills, bvFTD patients exhibited lower accuracy on identifying moral emotions –pity, embarrassment, and indignation– than AD patients, despite null differences in basic emotions. Subsequent discriminant analysis revealed that this differential pattern classified patient groups more accurately (74%: 65% bvFTD and 83% AD) than individual cognitive (59%) and executive (51%) measures. Crucially, between‐group classification substantially improved when combining the three measures mentioned above (79%: 68% bvFTD, 90% AD). In both groups, pity, embarrassment, and indignation identification correlated with reduced grey matter volumes in regions subserving social cognition and emotion processing, including the Rolandic operculum, the inferior and middle temporal gyri, and the postcentral gyrus (exclusive to bvFTD).ConclusionThese results suggest that bvFTD patients exhibit moral emotion impairments as compared with AD patients. Particularly, pity, embarrassment, and indignation emerged as useful measures to patients' classification. Such findings contribute to a better understanding of the structural correlates of moral emotional deficits in bvFTD patients while highlighting the potential benefits of integrating this domain into the standard cognitive and executive assessment for a more accurate differential diagnosis.
Acute peripheral inflammation does not change cerebral glucose metabolism
Authors: Machado Luiza Santos , dos Santos Camila N. , da Rocha Andreia Silva , Fontana Igor C. , Bellaver Bruna , Leonardi Bianca F. , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Zimmer Aline R. , Zimmer Eduardo R. 
Published: December 2021

AbstractBackgroundNeuroinflammation is a phenomenon already described in the brain of Alzheimer's disease (AD) individuals, with sustained neuroinflammatory response being detrimental. The effect of peripheral inflammation in AD is less understood. In fact, central nervous system (CNS) is protected from peripheral inflammation by the blood‐brain barrier. However, we recently demonstrated that severe sepsis causes acute brain metabolic disturbances, evidencing the CNS invasion of inflammatory mediators may affect brain function. Nevertheless, whether mild acute peripheral inflammation affects brain metabolism remains unclear. Objective: Here, we aimed at investigating the impact of mild acute peritonitis on brain energetic metabolism. Hypothesis: We hypothesized that mild peripheral inflammation will cause widespread brain glucose hypometabolism.MethodAdult male Wistar rats were randomly separated into carrageenan group, a model of mild acute peripheral inflammation (n=6), and control group (n=6). Peritonitis was induced by the administration of 500 µg of intraperitoneal (i.p.) carrageenan, while the control group was i.p. injected with 500 µl of saline. In vivo cerebral glucose metabolism was assessed using (18F)FDG‐microPET 4 h after inflammatory induction, which represents the first peak of inflammation. The peripheral inflammatory process was evaluated by analyzing the peritoneal lavage in a Flow Cytometer 48 h after the scanning i.p. injections, the second of peak of inflammation,ResultThe animals treated with carrageenan presented a 5‐fold increase in macrophages numbers (p<0,05) and a 2‐fold increase in monocytes numbers (p>0,05). However, our data showed that carrageenan‐induced peripheral inflammation did not cause acute changes in the whole brain glucose metabolism (p>0,05). Further regional analysis, in frontal and temporoparietal cortices, striatum, hippocampus, cerebellum, thalamus and hypothalamus, did not identify any difference between groups.ConclusionMild acute peripheral inflammation does not change brain glucose metabolism. Further evaluation aiming to investigate long‐term consequences of sustained mild inflammation are needed.
From research to realization: How a Texas health plan implemented an academic model of care for Alzheimer's disease
Authors: Stringer Cody , Smithroat Noemi , Samus Quincy M , Johnston Deirdre 
Published: December 2021

AbstractMIND at Home is a comprehensive, home‐based care coordination intervention for people with Alzheimer’s disease or related dementias (A/D) who live in the community and for their family caregivers. Developed by researchers at Johns Hopkins University (JHU), the model has been shown to extend the time a person with A/D remains at home for almost two years, as well as improved quality of life and quality of care and reduced caregiver burden. The MIND at Home pilot at Superior HealthPlan is a collaboration between Centene Corporation, JHU, and Superior HealthPlan (Superior). The goal of the MIND at Home pilot is to adapt, implement, and evaluate the impact of MIND at Home within Superior’s Medicaid population. The pilot is structured as an interventional study of the MIND at Home program versus a propensity score‐matched (PSM) comparison group receiving standard‐of‐care. The duration of the pilot is approximately 12 months, with longitudinal follow‐up at 18 and 24 months. The pilot population includes Superior HealthPlan Medicaid members (receiving Long‐Term Services & Supports) who are community‐residing and have a confirmed diagnosis of A/D. The study has enrolled approximately 300 participants who have received the intervention. An analysis of claims data for participants receiving the MIND at Home intervention indicates the program increased primary care utilization (+10.0%) while reducing emergency department (ED) utilization (‐15.8%), polypharmacy (‐5.0%), and total spend (‐1.35%). Consumer survey results indicate high levels of satisfaction among both pilot participants and their family caregivers and case studies anecdotally illustrate the significant impacts the MIND at Home program has had on participant and caregiver quality of life. Preliminary outcomes of the pilot indicate the MIND at Home program reduces high cost healthcare utilization – particularly ED and polypharmacy – and overall participant costs. Additional outcomes illustrate participants are highly satisfied with the MIND at Home program and have experienced dramatic increases in quality of life. This pilot showcases the value of operationalizing this evidence‐based academic care model for A/D in a Medicaid population and that collaboration across academic research, industry, and government‐sponsored healthcare programs can result in improved outcomes for individuals with A/D.
Dementia‐related agitation in Portuguese public hospitals: A retrospective analysis of 6,586 hospitalization episodes
Authors: Ferreira Ana Rita , Gonçalves‐Pinho Manuel , Simões Mário Rodrigues , Freitas Alberto , Fernandes Lia 
Published: December 2021

AbstractBackgroundDementia‐related agitation (DRA) is highly prevalent, disruptive and distressing, being a key cost‐driver of dementia care due to the high risk of emergency hospital admissions and prolonged hospitalizations. These events often prove harmful for dementia patients, resulting in multiple adverse outcomes that heighten the dementia burden. Although emerging studies support the societal and economic toll agitation places on patients, families and healthcare systems, more population‐based studies are needed on how DRA affects healthcare utilization. Thus, this study aimed to describe the hospitalizations with DRA held in mainland Portuguese public hospitals from 2010‐2015.MethodA retrospective observational design was used to analyze a nationwide database officially provided by the Portuguese Administração Central do Sistema de Saúde, IP (ACSS). This database comprises routinely collected healthcare data originally obtained for administrative purposes in all mainland Portuguese public hospitals, including International Classification of Diseases Ninth Revision Clinical Modification (ICD‐9‐CM) diagnostic codes. All inpatient episodes with age ≥65 years and a proxy DRA code of dementia with behavioral disturbance (ICD‐9‐CM 294.11, 294.21), were identified. Descriptive statistics were used to summarize the data.ResultOverall, 6 586 DRA inpatient episodes were analyzed. Most of these were associated with female patients (58.1%), with a mean age of 81±7 years, who have been admitted due to delirium, dementia, amnestic and other cognitive disorders (22.0%), pneumonia (15.0%), urinary tract infections (8.4%), acute bronchitis (5.3%), and acute cerebrovascular disease (4.1%). The median length of stay was 9 days (Q1‐Q3: 5‐17), and a total of 831 patients (12.6%) died during hospitalization. The mean estimated charges per episode were 2 916.5€, representing a total of 19 208 069€ during the study time‐frame.ConclusionResults corroborate the clinical and economic DRA impact. Nevertheless, data also suggest that a great share of admissions was due to preventable causes, which could have been managed with ambulatory treatment, thereby preventing harmful hospitalizations. To our knowledge, this is the first attempt to characterize how Portuguese patients with DRA use healthcare services, providing useful information to project future healthcare needs. Support: FCT [PD/BD/114555/2016], ERDF through operation POCI‐01‐0145‐FEDER‐007746 funded by COMPETE2020, National Funds through FCT within CINTESIS (UID/IC/4255/2013; UIDB/4255/2020).
No effect of exercise on AD‐related cognition in older African Americans: Program for African American Cognition and Exercise (PAACE)
Authors: Carmichael Owen T , Gwizdala Kathryn L. , Brouillette Robert , Beyl Robbie , Johnson William , Hebert Callie , Carter Leah , Harris Melissa , Newton Robert L 
Published: December 2021

AbstractBackgroundLower levels of physical activity (PA) are associated with greater risk of cognitive decline and AD, and some studies suggest that interventions that increase PA engagement lower risk of cognitive decline and AD. However, interventions to date have largely not included substantial representation of African Americans.MethodThe Program for African American Cognition and Exercise (PAACE) randomized 56 sedentary African American adults in the Baton Rouge, Louisiana area (mean age ± s.d.: 69.2 ± 3.4 years) to a physical activity group (PAG) or successful aging group (SAG). The PAG aimed to increase moderate to vigorous PA to national guideline levels over 12 weeks by providing supervised PA 2 days per week (90‐120 minutes/week) at local YMCAs along with 30‐60 minutes/week of home‐based PA. The SAG completed one 60‐minute educational session on successful aging per week for 12 weeks. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was assessed before and after the intervention. ANOVA models assessed pre‐ to post‐intervention RBANS total scale and sub‐scale score changes, as well as differences between PA and control arms in these changes.ResultGroups were well matched by age, sex, BMI, employment, education, and income. The SAG increased scores on the RBANS overall scale and scales of visuospatial function, immediate memory, and delayed memory, along with the story memory, figure copying, coding, and figure recall sub‐scales (all p<.05). The PAG increased scores on only the list learning sub‐scale (p=.047). Scores on the overall scale (p=.034) and story memory sub‐scale (p=.0008) increased significantly more in the SAG than in the PAG. No RBANS scores increased significantly more in the PAG compared to the SAG.ConclusionA 12‐week PA promotion program among community‐dwelling older African American adults provided significant cognitive benefits to an educational control group, and minimal benefits to those engaged in PA. Possible contributors to these results include inadequate PA stimulus in the PAG, and beneficial health behavior changes or cognitive stimulation in the SAG. Future research is needed to fully understand cognitive effects of PA interventions among older African Americans.
Efficacy of soluble epoxide hydrolase inhibition in a rat model of Alzheimer’s disease
Authors: Di Lucente Jacopo , Freitas Hercules R , Wagner Karen M , Hammock Bruce D. , Maezawa Izumi , Jin Lee‐Way 
Published: December 2021

AbstractBackgroundEpoxy fatty acids (EpFAs) are cytochrome P450‐dependent derivatives of PUFAs with potent anti‐inflammatory, pro‐resolving properties. However, their activities are extremely short‐lived as soluble epoxide hydrolase (sEH) quickly converts EpFAs to pro‐inflammatory diols. Here we test the hypothesis that inhibition of sEH is a potential therapeutic approach for Alzheimer’s disease (AD) via increasing the anti‐inflammatory actions of EpFAs in the brain.MethodThe functional expression of sEH in the TgF344‐AD model of AD and the human AD brain tissue samples, compared with control brain samples, was studied using qPCR, immunohistochemistry, and Western blotting. An orally available specific sEH inhibitor called 1770 was investigated for its effects on rectifying AD‐like deficits by treating 12 months old TgF344‐AD mice with 3 mg/kg/day 1770 via drinking water for 4 months and evaluating them by neurobehavioral, electrophysiological, and neuropathological assessments.ResultsEH was found to be overexpressed in both TgF344‐AD rat and human AD brains. All assessments conducted in the open field maze showed no significant differences between groups. We observed sensorimotor gating deficits in TgF344‐AD rats using acoustic startle response and prepulse inhibition task, which were reversed by 1770 treatment. We further observed deficits in novel object recognition and step‐through passive avoidance tests in TgF344‐AD rats, which were also mitigated by 1770 treatment. Consistent with enhanced memory performance, 1770 treatment rectified hippocampal long‐term potentiation deficits seen in TgF344‐AD rats. Immunohistochemical stains showed that 1770 treatment reduced microglial activation and Aβ amyloid load. Transcriptomics profiling is being conducted to further analyze mechanisms induced by 1770.ConclusionBased on our rat model data and previous data using cell and mouse models, sEH inhibition is a promising therapeutic approach to AD. Investigating the pathways for EpFAs production, degradation, and signaling may provide exciting new mechanisms and therapeutic targets for chronic neuroinflammatory conditions such as AD.
Adjustment to test, risk and diagnostic disclosures in people with mild cognitive impairment: An observational cohort study
Authors: Saunders Stina , Muñiz‐Terrera Graciela , Russ Tom C , Ritchie Craig W. 
Published: December 2021

AbstractBackgroundMild cognitive impairment (MCI) is a condition with slight decline in cognition, but unaffected daily functioning. Given its uncertain prognosis, communicating this in clinical consultations with patients is crucial. Our aim was to understand the impact of clinical risk reporting to individuals with newly identified MCI, focusing on changes in cognition, anxiety, psychological well‐being and adjustment to illness in the short and long term.MethodThis is a longitudinal mixed methods study. Participants who were referred to a memory clinic with a suspected MCI were recruited from across South‐East Scotland. Baseline assessments (June 2018‐July 2019) were conducted before the MCI risk disclosure. Follow up assessments started after individuals were disclosed of memory assessment results and were carried out over two years (completed by May 2021 due to COVID‐19 restrictions). The primary outcome measures are neuropsychological assessment (RBANS), anxiety assessment (STAI) and results from semi‐structured interviews.ResultThere are 63 individuals recruited (men = 25, 40%; women = 38, 60%); average age 77 years, SD=6.76; average years of education 13 (mode 10). At baseline, the mean RBANS score was 87 (SD=15.79); STAI score 81 (SD=20.59). A higher RBANS score at baseline was predicted by more years of education and higher score in ‘Attitude toward present treatment & doctors.’ Being identified as having MCI was predicted by higher perceived deficits and feelings of depression and worry. Longitudinal analyses of adjustment to MCI will be presented at the conference. Initial results of the interviews show that the concept of MCI is perceived with mixed feelings, with the immediate response to disclosure more positive and as time goes on, the initial perception shifting.ConclusionBaseline RBANS results are consistent with other research on the same clinical population. This study gives empirical evidence on the impact of being informed of test results at the pre‐dementia or early dementia stages where future prognosis is uncertain. The longitudinal data will be used to identify modifiable risk factors for adjusting to MCI disclosure well or less well.