bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive impairment one year after hospitalization due to COVID‐19 infection in Brazil: preliminary results.
Authors: Sousa Danielle Calil , Leite Arnaldo Santos , Faria Barbara Caroline Dias , Sacramento Luiz Gustavo Guimarães , Marinho Carolina Coimbra , Caramelli Paulo 
Published: December 2022

AbstractBackgroundPersistence of symptoms or development of new symptoms after SARS‐CoV‐2 infection is an increasingly recognized problem and the long‐term post‐COVID‐19 outcome and the effects on cognitive function remain poorly understood. This study aims to investigate the long‐term cognitive effects and impacts of COVID‐19 with a special focus on a population with low education and low socioeconomic status.MethodCross‐sectional cognitive assessment of participants with severe forms of Covid‐19 one year after hospital admission. Until now, 187 of 322 patients underwent TICS‐M for brief telephone cognitive screening one year after hospitalization for COVID‐19 in 3 public hospitals in Belo Horizonte, Brazil. This sample was divided into two groups according to scores on the TICS‐M screening test: with or without cognitive impairment. 26 participants were selected by convenience for neuropsychiatric assessment, namely 13 with abnormal TICS‐M scores (cases) and the other 13 controls. They were submitted to the following tests and scales: Addenbrooke’s Cognitive Examination‐Revised (ACE‐R), Symbol Digit Modalities Test (SDMT), Free and Cued Selective Reminding Test (FCSRT‐IR), Hospital Anxiety and Depression Scale (HADS) and Impact of Events Scale‐Revised (IES‐R).ResultThere were no significant differences between groups for age, sex, educational level, need for intensive care unit or use of anticholinergics or sedatives. Although the comparison of SDMT between the groups showed no statistical difference (p = 0.999), all participants showed lower performance compared to normative data. Cases presented lower scores than controls in ACE‐R total (p = 0.034) and in the subdomains Attention and Orientation (p = 0.002), as well as in delayed total recall of the FCSRT‐IR (p = 0.039). Moreover, participants with lower HAD‐D scores had worst performance in Attention and Orientation subdomains of the ACE‐R (p = 0.003).ConclusionOur study shows impairment in global cognition, attention, orientation and episodic memory in individuals previously hospitalized for COVID‐19 infection who presented low scores on TICS‐M. Performance in processing speed tests was impaired among both groups in relation to normative data. Cognitive and mood analyses after COVID‐19 infection can provide information for improving healthcare of these individuals.
Juvenile concussion results in accelerated aging:A diffusion MRI investigation
Authors: Lee Jeong Bin , Grande Beatriz Rodriguez , Fournier Marie‐Line , Clément Tifenn , Trotier Aurélien J , Miraux Sylvain , Marchi Nicola , Badaut Jerome , Obenaus Andre 
Published: December 2022

AbstractBackgroundJuvenile mild traumatic brain injury (jmTBI) has the potential to elicit cognitive, adaptive, and socio‐behavioral decrements. Unknown is how early life concussions can lead to enduring effects into late adulthood. Studying jmTBI progression from an early concussive event to long term deficits in adulthood is critical for outcome prediction and the development of appropriate treatments. We hypothesized that a single jmTBI leads to an altered brain maturation, thereby producing temporally evolving microstructural deficits that eventually lead to late‐in‐life cognitive and behavioral deficits.MethodsWe investigated the long‐term effects of jmTBI in C57Bl6 mice at postnatal day 17 and mapped the temporal evolution of alteration in long‐term behavior and cognitive outcomes. Diffusion‐tensor MRI (DTI) and structural MRI were examined at 7 temporal epochs from 1 to 18mo post‐concussion. Regional MRI tissue analysis was performed using the AMBC mouse atlas. Confirmatory immunohistochemistry was also undertaken.ResultsjmTBI led to increased glial fibrillary acidic protein (GFAP) and neurofilament‐light (NFL) in blood samples and impaired spatial learning and memory was evident at 18mo. Extensive DTI longitudinal analysis from 1 to 18mo post‐concussion revealed that jmTBI produced temporally dependent deficits that were concurrent with behavioral impairments. DTI findings were concentrated at earlier timepoints (1‐3 m) and were correlated 10 behavioral deficits at 18m.ConclusionWe demonstrate that a single juvenile concussion early in life leads to lasting behavioral impairments later in life and which are linked to early regional tissue deficits. Our work not only establishes that juvenile concussions are chronic in nature with the potential to produce long‐lasting effects but provides an unprecedented insight into how an early concussions may produce adverse effects later in life.
Contribution of astrocytic MMP9 toward progression of VCID pathology
Authors: Early Alexandria N , Weekman Erica M , Lee Tiffany , Wilcock Donna M 
Published: December 2022

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes of dementia. High levels of plasma homocysteine or hyperhomocysteinemia has been characterized as a risk factor for VCID however, the mechanism underlying the connection between hyperhomocysteinemia and development of VCID pathology remains elusive. I hypothesize that hyperhomocysteinemia initiates a pro‐inflammatory cascade that increases the activity of MMP9 causing both perivascular astrocytes to dissociate from their vessels and initiating the degradation of endothelial cell tight junction proteins, leading to blood brain barrier dysfunction and the progression toward VCID pathology.MethodFor in vivo studies, C57BL6 WT and MMP9KO mice were placed on a control diet or a diet deficient in folate, vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia for 4, 8, 12, and 16 weeks. For in vitro, experiments, primary astrocytes from WT and MMP9KO mice were treated with a 50μM homocysteine stimulus or an inflammatory stimulus (TNF‐a, IL‐1b and C1q) for 48 hours and the conditioned media was collected. This homocysteine or inflammatory astrocyte conditioned media was then used to treat WT endothelial cells. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes while histology was used to identify changes in astrocytic end‐feet proteins, tight junction proteins, vascular density and microhaemorrhages. Both gel and in situ zymography were used to assess proteinase activity of MMP9 and related gelatinases. Western blots were used to investigate substrates of MMP9 including claudin, occludin and β‐dystroglycan. Behaviour was assessed using rotarod, novel object recognition and spontaneous alternation testing. Transendothelial electrical resistance and sodium fluorescein assays were used to measure the integrity of endothelial cell tight junctions in vitro.ResultStudies are underway to examine changes in cognition, microhaemorrhages, neuroinflammation, astrocyte end‐foot integrity, tight junction protein integrity and activity of MMP9.ConclusionCollectively, our findings suggest that astrocytic MMP9 may play an integral role in the mechanism associating homocysteine induced neuroinflammation with vascular pathogenesis leading to VCID, highlighting this pathway as an important subject for future study.
Role of extracellular vesicles in early synaptic dysfunction in AD
Authors: Prada Ilaria , Gabrielli Martina , Joshi Pooja , Falcicchia Chiara , D'Arrigo Giulia , Rutigliano Grazia , Tonoli Elisa , Battocchio Elisabetta , Zenatelli Rossella , Tozzi Francesca , Verderio‐Edwards Elisabetta , Radeghieri Annalisa , Arancio Ottavio , Origlia Nicola , Verderio Claudia 
Published: December 2022

AbstractBackgroundSynaptic dysfunction is an early mechanism in Alzheimer’s Disease (AD) which involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. We hypothesised that large extracellular vesicles (EVs) released by microglia exposed to and carrying Aβ42 (Aβ‐EVs) may be responsible for these early events in AD.MethodCombining optical manipulation with time lapse imaging we placed single Aβ‐EVs and ctrl‐EVs (released by microglia not exposed to Aβ) on axons or dendrites of RFP‐positive cultured neuron to test both the dynamics of their interaction with neurons and their effects on the synapse. Then, EVs were stereotaxically injected into the mouse entorhinal cortex (EC), one of the most vulnerable regions in AD, and long‐term potentiation (LTP) was measured in the EC and in its main target region, the dentate gyrus of the hippocampus (DG), through field potential extracellular recordings in cortico‐hippocampal brain slices. Finally, taking advantage of high‐resolution accurate‐mass spectrometry SWATH™‐MS, we investigated the molecular differences between ctrl‐EVs and Aβ‐EVs.ResultAβ‐EVs were able to move along the axonal surface more efficiently than ctrl‐EVs and predominantly in an anterograde direction. They locally altered dendritic spine morphology in vitro and impaired LTP in vivo. One hour after injection in the EC, LTP was impaired in the EC of brains injected with Aβ‐EVs but not ctrl‐EVs. However, 24h after Aβ‐EV injection, LTP was impaired also in the DG, indicating a spreading of synaptic dysfunction between the two connected regions. Results were reproduced using large EVs released by microglia exposed to naturally secreted Aβ oligomers, whereas neither Aβ alone nor inflammatory EVs devoid of Aβ were able to propagate LTP impairment. Importantly, when Aβ‐EV motility was limited by annexin‐V coating, no propagation of LTP deficit occurred along the EC‐DG circuit. Proteomic analysis provided insights into the possible molecular mechanisms underneath Aβ‐EV extracellular motion at the neuronal surface.ConclusionOur data provide evidence of the involvement of microglial EVs in early synaptic dysfunction, through a new mechanism ‐ extracellular motion at the neuronal surface ‐ not implying EV internalization, paving the way for novel therapeutic strategies.
Development and systematic evaluation of high resolution PD‐weighted, T2‐weighted, and T2 map templates of the MIITRA atlas for use in studies on older adults
Authors: Ridwan Abdur Raquib , Niaz Mohammad Rakeen , Wu Yingjuan , Zhang Shengwei , Bennett David A , Arfanakis Konstantinos 
Published: December 2022

AbstractBackgroundAtlas based MRI investigations involving PD‐weighted (PDw), T2‐weighted (T2w) MRI sequences on older adults typically utilized younger adult templates such as those of the ICBM. Additionally, a thorough quantitative assessment of how available standardized PDw and T2w templates perform on aging population has not yet been performed. Here a new standardized high resolution PDw, T2w and T2 map templates of the MIITRA atlas dedicated for studies on older adults was developed using concepts of super‐resolution and sparse‐representation and compared to other available standardized templates in terms of image quality, inter‐subject spatial normalization accuracy and representativeness of the older adult brain.MethodT2‐weighted multi‐echo spin‐echo brain MRI (0.5mmx0.5mmx3mm isotropic, TE=20,40,60,80,100ms) and its corresponding T1‐weighted (isotropic 1mm) data obtained from the 400 non‐demented older adults (65‐95 age range, male:female=1:1) participating in the construction of the MIITRA atlas were used in this work. Additionally, subject T2 maps were constructed by fitting the T2 decay equation. The template construction involved reconstruction of high resolution voxels of T2‐weighted data utilizing nonlocal super‐resolution upsampling technique, mapping of each of the five echo (TE=20,40,60,80,100ms) separately using combined iterative T1‐weighted and DTI spatial normalization based transformations on a super‐resolution grid followed by patch‐based sparse representation to construct our T2‐weighted templates of the MIITRA atlas (Fig.1).The first echo PD‐weighted and the third echo T2‐weighted templates were compared to other available templates in terms of image sharpness and inter‐subject spatial normalization accuracy achieved when used as references for normalization of 30 ADNI PD‐weighted and T2‐weighted participants.ResultThe new PD and T2 weighted templates of the MIITRA atlas demonstrated higher image sharpness compared to the other templates, as exhibited by larger high spatial frequency content in the normalized power spectra (Fig. 2A,B,C,D). Inter‐subject spatial normalization was higher when using the new templates compared to the other templates (Fig.3,4). The new templates required the least spatial deformation for normalizing ADNI data (Fig.5A,B).ConclusionWe conclude that the new PD‐weighted and T2‐weighted templates of the MIITRA atlas are characterized by superior image quality, require lower deformation and allow for higher spatial normalization accuracy for use in studies on older adults such as the ADNI datasets.
IMPROVING DEMENTIA CARE THROUGH DIGITAL CAREGIVER EMPOWERMENT: DURABLE CLAIMS‐BASED OUTCOMES DEMONSTRATED IN A PRAGMATIC REAL‐WORLD TRIAL
Authors: Soenksen Dirk , Kleinman Nathan 
Published: December 2022

AbstractObjectiveThe Ceresti Digital Caregiver Empowerment Program (DCEP) was deployed to 164 family caregivers of Medicare Advantage patients with ADOD. The primary objective of this pragmatic trial was to demonstrate that increasing the knowledge, skills and confidence of family caregivers (e.g., spouses, adult children) via personalized education, proactive coaching and remote monitoring—delivered via an app on a dedicated tablet computer—reduces avoidable patient hospitalizations. Durability of claims‐based outcomes was also studied. Caregiver engagement, caregiver satisfaction and caregiver mental health were also trackedMethodsPatients were included in the claims analysis if their caregiver was enrolled in the DCEP for at least 45 days. Patient outcomes were compared to outcomes from a 3:1 propensity matched comparison group, post‐index, from the DCEP start date to the end of claims. Comparison group members were matched to enrollees on demographics, pre‐index utilization and costs, and other factors, including the patient’s frailty index. The first 30‐days post‐index were deemed a “transition” period. The impact of the DCEP was determined by comparing the 6‐month pre‐index averages to outcomes from the 30‐day post‐index period using the “difference‐in‐differences” approach (Figure 1).The index date for program enrollees was their DCEP start date. For matched comparison group patients, the index date was the program start date of the enrollee to whom the comparison group member is matched. The DCEP was personalized for each caregiver/patient dyad using predictive models applied to claims data.Results ‐ Patient OutcomesTable 1 summarizes statistically significant (p‐values < 0.05) monthly reductions in utilization and costs for patients enrolled > 45 days, and enrolled high utilizers enrolled > 45 days (PMPM = per member/patient per month). High utilizers are patients with at least one hospitalization or two ED visits in the prior 24 months. Results were durable through 9 months post‐index (Figure 3).ConclusionsEmpowering family caregivers of patients with ADOD in a personalized DCEP provides durable reductions in patient hospitalizations and medical costs.
APOE genotype alters the lipid droplet proteome and modulates droplet dynamics
Authors: Smith Cathryn T , Friday Cassi , Devanney Nicholas , Allenger Elizabeth J. , Cornea Ana Maria L/K , Gordon Scott , Johnson Lance A 
Published: December 2022

AbstractBackgroundThe microglial immune response is a significant contributor to Alzheimer’s disease (AD) pathophysiology and neurodegeneration. Aging microglia accumulate lipid droplets (LDs), have high levels of reactive oxygen species, secrete pro‐inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset AD, and is associated with heightened neuroinflammation and increased LD formation. We hypothesize E4 microglia have increased LD formation under basal conditions and a higher capacity to form LDs under stress, resulting in greater pro‐inflammatory cytokine production. We characterized LD development in microglia in the context of APOE genotype and analyzed LD surface proteins and lipid content from control and lipopolysaccharide (LPS) stimulated ApoE3 and ApoE4 mice.MethodPrimary microglia were isolated from mice expressing human ApoE3 and ApoE4. Microglia were exposed to 250uM oleic acid (OA), 10ug/mL LPS, OA+LPS, dead N2A cells, or dead N2As+LPS. ApoE3 and ApoE4 expressing mice were injected with saline (control) or LPS (5mg/kg) and perfused at 24h. Livers were extracted, the LD enriched supernatant fraction was collected after centrifugation, and proteomic and lipidomic analyses were performed.ResultPrimary microglia from ApoE4 mice accumulated more LDs at baseline, with exogenous OA, LPS stimulation, and N2As as a percentage of E3 control across multiple experiments (E3 v E4 p‐values: baseline, 0.0317; LPS, 0.0032; OA, 0.0277; N2A, 0.0192). Western blots on LD fractions confirm LD enrichment by surface protein, PLIN2, along with increased expression of PLIN2 (i.e. more LDs) in E4 LPS mice. Proteomics reveal LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for proteins involved in lipid b‐oxidation.ConclusionE4 microglia accumulate more LDs compared to E3 microglia under all conditions tested. The proteomic profile of E4 liver LDs support the hypothesis that E4 expression increases inflammation under basal conditions, and upon stimulation, causes a more robust response. Increased LD formation is present in non‐aged, non‐diseased E4 cells, suggesting preclinical dysfunction associated with the highest risk APOE genotype. A better understanding of LD dynamics within these cells and their functional implications can provide targets to improve E4‐related outcomes.
Association of long‐term exposure to air pollution and dementia risk: the role of homocysteine, methionine
Authors: Rizzuto Debora , Hooshmand Babak , Vetrano Davide Liborio , Wu Jing , Grande Giulia 
Published: December 2022

AbstractBackgroundGrowing evidence associates long‐term exposure to air pollution with dementia. The biological mechanisms behind this association are yet unclear. We aimed to investigate the role played by homocysteine and methionine in the association between air pollution and dementia.MethodData from 2512 dementia‐free individuals were derived from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC‐K). Two major air pollutants (particulate matter ≤2.5µm, PM2.5 and nitrogen oxides, NOX) were assessed yearly from 1990, using dispersion models for outdoor levels at residential addresses. The hazard of dementia was estimated using Cox models. The potential mediating or modifying effects of homocysteine and methionine were analysed through the counterfactual approach.ResultOver a mean follow‐up time of 5.18 years (SD: 2.96), 376 incident dementia cases were identified. We observed an up to 70% increased hazard of dementia per unit increase in PM2.5 levels during the previous five years (HR: 1.71; 95%CI: 1.33‐2.09). We found that approximately 50% (95%CI: 8.9‐97.7) of the total effect of PM2.5 on dementia was due to mediation (7.5%; 95%CI:1.8%‐13.3%) and/or interaction (50%; 95%CI: 5.0%‐ 94.9%) with homocysteine. Higher levels of methionine reduced the dementia risk linked to PM2.5 exposure by 31% (HR: 0.69; 95% CI: 0.56 – 0.85). No statistically significant mediation effect was found through methionine in the association between PM2.5 and dementia. Similar but attenuated results have been obtained for NOx.ConclusionHigh levels of homocysteine enhanced the dementia risk associated with air pollution exposure, whereas high methionine reduced such a risk.
Stable Isotope Labeling Kinetics (SILK) tracing of neurofilament light in stem cell‐derived neurons
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Bateman Randall J. , Zetterberg Henrik , Mills Kevin , Wray Selina , Paterson Ross W. 
Published: December 2022

AbstractBackgroundNeurofilament light polypeptide (NfL) is a basic component of intermediate filaments in neurons that is released from damaged and/or degenerated neuronal axons. As such, NfL levels in CSF and serum are elevated in several neurodegenerative diseases, and have been proposed as a promising biomarker of axonal damage. However, whether NfL’s extracellular release results from passive events or active mechanisms remains largely unknown. Kinetic labeling at the step of protein translation can inform about active translation vs. passive release processes and provide protein metabolism half‐lives and rates of production and clearance.MethodOur aim was to develop a method to study NfL turnover rates using stable isotope labeling kinetics (SILK) in human induced pluripotent stem cell (iPSC)‐derived neurons. We added 13C6‐leucine, the tracer, to the neuron cultures (“pulse”) for four weeks, followed by medium exchange with 12C6‐leucine, the tracee, for an additional four weeks (“chase”). Samples were collected during both the pulse and chase phases of the experiment. 13C6‐leucine incorporation and the levels of labeled NfL in cell lysates and conditioned media from two independent neuronal inductions were analyzed by ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) and the tracer‐to‐tracee ratio (TTR) and mole percent excess (MPE) calculated.ResultWe detected ten leucine‐containing peptides unique to NfL in neuronal cell lysates, which are present within the rod‐domain of the protein. These peptides showed different rates of 13C6‐leucine incorporation (reaching up to 69% MPE).ConclusionPreliminary data on the monitoring of these peptides suggest that NfL is turned over at a slow rate in iPSC‐. Tracking of both intracellular and extracellular NfL in neurons derived from healthy control individuals, as well as cells with mutations implicated in neurodegenerative diseases, are expected to shed light into the dynamics of NfL turnover in both physiological and pathological conditions. This will be critical for interpreting NfL in response to disease‐modifying therapies.