bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patients with Alzheimer’s disease dementia show partially resilient parietal “HUBS” modeled from resting‐state alpha electroencephalographic rhythms
Authors: Lopez Susanna , Percio Claudio Del , Lizio Roberta , Noce Giuseppe , Padovani Alessandro , Nobili Flavio Mariano , Arnaldi Dario , Famà Francesco , Moretti Davide , Soricelli Andrea , Ferri Raffaele , Buttinelli Carla , Giubilei Franco , Güntekin Bahar , Yener Görsev , Stocchi Fabrizio , Vacca Laura , Bonanni Laura , Babiloni Claudio 
Published: June 2023

AbstractBackgroundGraph theory models a network by its nodes and connections. “Degree” hubs reflect node centrality, while “connector” hubs are those linked to several clusters of nodes. Here we compared hubs modelled from measures of interdependencies of between‐electrode resting‐state eyes‐closed electroencephalography (rsEEG) rhythms in normal old (Nold) and Alzheimer’s disease dementia (ADD) participants. As ADD is considered as a “network disease” and is typically associated with abnormal rsEEG delta (< 4 Hz) and alpha rhythms (8‐12 Hz) over associative posterior areas, we predicted abnormal posterior hubs from measures of interdependencies of those rhythms in ADD as compared to Nold participants.MethodTo report robust results, we measured interdependencies of rsEEG rhythms from delta to gamma bands (2‐40 Hz) by both bivariate linear lagged connectivity and multivariate (directional) isolated lagged effective coherence. Furthermore, we used three different definitions of “connector” hub.ResultConvergent results showed that in both Nold and ADD groups, there were significant parietal “degree” and “connector” hubs derived from alpha rhythms. These hubs had a prominent outward “directionality” in the two groups, but that “directionality” was lower in ADD than Nold participants (Figure 1).ConclusionIndependent methodologies and hub definitions suggest that ADD patients may be characterized by low outward “directionality” of topologically partially resilient parietal “degree” and “connector” hubs derived from rsEEG alpha rhythms. Combined use of independent methodologies in rsEEG studies may produce robust results in clinical applications in ADD patients.
Dual tasking paradigm in clinical stages of early Alzheimer’s disease
Authors: Sorinas Jennifer , Cormack Francesca K , Taptiklis Nick , Vallejo Vanessa , Snædal Jón , Jonsdottir Maria K. , Hannesdottir Kristin , Curcic Jelena 
Published: June 2023

AbstractBackgroundIn Alzheimer’s disease (AD) both motor and cognitive domains are impaired [1‐2]. However, these domains are usually assessed independently, even when performing dual‐task (DT) paradigms, the cognitive‐motor interaction (CMI) is not taken into account which may lead to misinterpretation of the patient’s global state. To date, there are no precise markers to neither detect subtle signs of pre‐clinical neurodegeneration nor accurately monitor disease progression.MethodWe have evaluated the motor and cognitive components of a DT paradigm concurrently (Figure 1). 50 participants, aged 60 to 80 years, were included in the study, distributed across four cohorts corresponding to progressive clinical stages of early AD [3]: 1) amyloid negative, cognitively healthy participants (control group), 2) amyloid positive pre‐symptomatic AD, 3) Mild Cognitive Impairment (MCI) due to AD and 4) mild AD. Two inertial measurement units (IMUs) (Physilog, GaitUp S.A.) were attached to each foot to measure gait parameters and a small microphone (Wireless GO, RØDE) was attached to the shirt to record counting. Both timing and gait features were extracted from raw data, however only conventional features, correct response rate (CRR) and gait speed, were considered for this abstract and were used to evaluate the CMI based on Plummer’s classification system [5]. Moreover two‐way ANOVA was carried out to evaluate the effect of cohort and cognitive load conditions on the CMI.ResultOur results show that there is a significant drop in performance at both the cognitive and motor tasks while performing DT and that this drop is more pronounced as we move toward stages of greater cognitive impairment and as we increase the cognitive load of the task (Figure 2). Moreover, CMI shows a cognitive‐priority trade‐off in all cohorts (better/similar counting while slower walking), but movement toward mutual interference effect (worst counting and slower walking) when increasing cognitive load and state of cognitive decline (Figure 3).ConclusionTo our knowledge, this is the first feasibility study assessing the CMI at preclinical and early clinical stages of AD. Our preliminary results suggest that the DT paradigm is a sensitive method to detect early signs of neurodegeneration and monitor AD progression.
Glial cell reactivity drives cognitive decline in LDLr‐/‐ mice: experimental evidences
Authors: Rodrigues Matheus Scarpatto , Farias Hemelin Resende , Schons Tainá , Machado Alessandra Gonçalves , Bast Rachel KSS , Engblom David , Budni Josiani , de Bem Andreza Fabro , de Oliveira Jade 
Published: June 2023

AbstractBackgroundFamilial hypercholesterolemia (FH) is a clinical condition characterized by increased plasma cholesterol levels, due to a mutation in the gene encoding the low‐density lipoprotein receptor (LDLr) in cells [Brown and Goldstein, 1984]. Importantly, clinical evidence indicates that FH negatively affects cognition and favors the development of neuropathologies [Ariza et al., 2016; Zambón et al, 2010], however, the mechanisms behind this relationship are still not fully understood. In this study we aimed to investigate the role of glial cell reactivity on the cognitive deficits related to the FH, as well as the possible neuroprotective effect of a pharmacological inhibitor of microglial cell activation.MethodFirstly, male 3‐months‐old and 14‐months‐old C57BL/6 wild‐type and LDLr knockout mice (LDLr‐/‐) mice brains were prepared for the evaluation of glial cell morphology by immunofluorescence. In addition, the mice’s hippocampus was removed to measure the immune content of synaptic and tight‐junctions proteins. Moreover, male and female 6‐months‐old C57BL/6 wild‐type and LDLr‐/‐ mice were treated with minocycline (50 mg/kg) or vehicle (saline) for four weeks. Afterwards, mice were submitted to behavioral tests.ResultMiddle‐aged LDLr‐/‐ mice (14‐months‐old) exhibited increased microgliosis in hippocampus, which was correlated with morphological change of microglial cells and astrocytes in this same brain region. Also, middle‐aged LDLr‐/‐ mice presented a reduction in the immune content of synaptophysin‐1 in the hippocampus. Moreover, young adult (3‐months‐old) LDLr‐/‐ mice exhibited reduced immune content of PSD95 in the hippocampus. Finally, the administration of minocycline to 6‐months‐old LDLr‐/‐ mice ameliorated the performance of hypercholesterolemic mice in hippocampal‐dependent memory tasks, without modifying their locomotor activity and metabolic parameters.ConclusionTaken together, our results demonstrated that FH alters the glial cell reactivity, which was associated with changes in synaptic proteins in the hippocampus. In addition, the pharmacological modulation of microglial cell reactivity ameliorated the hippocampal‐dependent memory in LDLr‐/‐ mice, suggesting that increased glial cell reactivity is a key event for HF‐related cognitive deficits.
Clinical outcomes of amyloid and tau markers according to vascular markers
Authors: Chun Min Young , Kim Young Ju , Choe Yeongsim , Park Yu Hyun , Kim Jinhee , Kim Hee Jin , Jeong Jee Hyang , Jang Hyemin , Seo Sang Won 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by amyloid beta (Aβ) aggregation [A] and tau aggregation reflecting neurofibrillary tangles [T]. These AD markers lead to neurodegeneration [N] and cognitive impairments. Recently, the ATN research framework of was presented by National Institute on Aging and Alzheimer’s Association. Cerebral small vessel disease (CSVD, [V]), which is one of most important cause of cognitive impairments, has an additive or synergistic effect on cognitive impairments with AD markers. In the present study, we investigated the frequency of ATV abnormalities in participants with varying degree of AD and CSVD markers. We also determined whether CSVD might synergistically affect cognitive decline with AD markers.MethodWe consecutively recruited 195 subjects (105 AD‐related cognitive impairment subjects, 86 subcortical vascular cognitive impairment subjects) from Samsung Medical Center. [A] and [T] positivities were determined by cut‐off values of Aβ and tau uptakes on PET using iterative outlier methods. [V] was assessed by the presence of severe white matter hyperintensity. All subjects underwent neuropsychological tests including Mini‐Mental State Exam (MMSE) and clinical dementia rating‐sum of boxes (CDR‐SOB). A linear mixed effect model was used to compare cognitive changes over time.ResultThe number of subjects of A‐T‐, A+T‐, and A+T+ groups were 16 (15.1%), 29 (27.4%), and 56 (52.8%) in the V‐ group; and 46 (51.7%), 33 (37.1%), and 8 (9.0%) in the V+ group. The linear mixed effects model analysis showed that A+/T+ were associated with worse cognitive decline, and its impact is higher in the V+ group than in the V‐ group (Figure).ConclusionOur findings suggested that there were interactive effects of AD markers and CSVD on cognitive decline. These findings demonstrate the importance of vascular factor management in patients with cognitive impairment and suggest that the ATV framework is useful in predicting cognitive decline in clinical practice.
Effects of APOE genotype on amyloid PET positivity according to cognitive status and ethnicity
Authors: Chun Min Young , Kim Bo‐Hyun , Kim Jinhee , Jeong Jee Hyang , Kim Hee Jin , Jang Hyemin , Seo Sang Won 
Published: June 2023

AbstractBackgroundAmong the various risk factors for Alzheimer disease (AD), apolipoprotein E (APOE) genotype ε4 is known to be a strong factor. On the other hand, ε2 is known to have a protective effect. It is not yet clear how amyloid positivity according to the APOE genotype differs by diagnostic criteria. Also, there were no studies showing the ethnic difference in the effects of APOE genotype on amyloid‐beta (Aβ) between American and Asian. The aim of this study was to investigate how Aβ positivity (Aβ+) according to APOE genotypes differs by ethnicity and cognition.MethodWe recruited 4,203 Korean subjects from multi‐centers in South Korea and 1,069 subjects from Alzheimer’s Disease Neuroimaging Initiative database. All subjects underwent neuropsychological tests, APOE genotype tests, and amyloid PET (FMM/FBB/AV45) scans. Subjects with the ε2/ε4 genotype were excluded due to the opposing effects of the ε4 and ε2 alleles. The degree of influence on amyloid positivity by each factor was analyzed by logistic regression.ResultThe frequency of Aβ+ in normal cognition (NC) group was higher in ADNI than in Korean group (p <0.001). Amnestic mild cognitive impairment and AD dementia (ADD) groups showed no difference in the frequency of Aβ+ between ADNI and Korean groups. Relative to APOE ε3/ε3 group, APOE ε4 carriers showed higher frequent Aβ+ regardless of cognitive status and ethnicity (Figure). ADNI and Korean groups showed APOE ε2 carriers less frequent Aβ+ in ADD but not in NC relative to APOE ε3/ε3 group.ConclusionOur findings suggested that there were no differences in effects of APOE ε4 genotype on Aβ+ between European and Korean. These findings will be helpful in predicting amyloid positivity and AD intervention according to APOE genotype and ethnicity.
Clinical outcomes of conversion to amyloid‐beta positivity in amyloid‐beta negative elderly
Authors: Kim Jun Pyo , Chun Min Young , Jeong Jee Hyang , Jang Hyemin , Seo Sang Won 
Published: June 2023

AbstractBackgroundEarly detection of amyloid beta (Aβ) accumulation has become important as Aβ accumulation begins before clinical symptoms appear. Previous longitudinal studies of Aβ‐negative (Aβ‐) people have shown that some of them convert to amyloid‐positive (Aβ+) and others remain amyloid‐negative. The clinical effects of conversion to Aβ+ have not been extensively investigated, yet. The aim of the study is to investigate the longitudinal cognitive changes according to conversion to Aβ+.MethodWe recruited subjects from 62 Korean subjects from Samsung Medical Center and 275 the Alzheimer’s Disease Neuroimaging Initiative database that were followed for more than three years. All subjects were amyloid PET negative and showed normal cognitive function at baseline. They were followed for more than three years and underwent amyloid PET and clinical dementia rating‐sum of boxes (CDR‐SOB). Longitudinal cognition changes according to conversion to Aβ+ were analyzed using a linear mixed effect model.ResultTwelve (4.4%) of Aβ‐ ADNI participants and three (4.8%) of Aβ‐ Korean participants were converted to Aβ+. The ADNI and Korean subjects showed that CDR‐SOB was significantly deteriorated in the converter group than in the non‐converter group (p = 0.034 for ADNI; p = 0.022 for Korean).ConclusionOur findings revealed that conversion to Aβ+ predicted worse clinical outcomes, suggesting that it is important to recognize potential candidates for primary prevention of AD.
Promoting patient‐centered‐care through a virtual reality medical school curriculum focused on dementia and end‐of‐life in the COVID Era
Authors: Negris Olivia R , Balas Johanna S. , Phelps Emily Broman , Washington Erin , Brennan Ann , Volgman Annabelle Santos , Fleischman Debra A , Aggarwal Neelum T. 
Published: June 2023

AbstractBackgroundThe COVID pandemic has brought death and dying to the forefront, contributing to the already high levels of physician burnout. Furthermore, there is a negative correlation between physician burnout and empathy. Due to time constraints of clinical rotations in traditional medical education, there are often shortcomings in students’ understanding of how to best manage and communicate with chronically or terminally ill patients. This study implements a distributive model of a virtual reality (VR)‐based curriculum, utilizing vignettes that portray a Latinx woman, Beatriz, with Alzheimer’s disease, and a veteran, Clay, with cancer transitioning to hospice from a first‐person perspective.MethodMedical and premedical students in Chicago were recruited (N = 12, 75% female, 58% White, 58% M2) and engaged in a self‐directed VR‐based curriculum, including Embodied Labs modules and corresponding lectures from expert physicians. Lecture content time was 2 hours 40 minutes and VR module time was 35 minutes, which students completed at their own pace prior to a Zoom group discussion. Participants completed a series of pre‐ and post‐surveys.ResultPreliminary qualitative analysis reveals participant‐perceived increased competencies in the following themes: medical knowledge and preparedness (100%), compassion and empathy (67%), communication and patience (50%), emotional connection and advocacy (50%), and family values and comfort (42%) after program completion. Moreover, 11/12 participant reflections either directly stated the value of this experience for their professional development or explicitly highlighted its utility within medical school curricula. Additional qualitative content analyses and quantitative statistics on the changes in pre‐ and post‐survey measures are forthcoming.ConclusionBurnout and reduced patient‐centered‐care have been identified as barriers to empathic delivery of care in the COVID era. Utilizing VR to develop a medical curriculum fosters increased compassion and empathy in the context of dementia and end‐of‐life care. This multi‐dimensional curriculum can be scaled and implemented virtually to mitigate the impact of burnout on empathy in trainees caring for patients during the pandemic. Future aims include formally integrating this model into a medical curriculum, targeting students early in their career before they are overwhelmed with burnout, and broadening content to include trainees from diverse medical professional programs and institutions.
Alzheimer’s disease perturbs gene‐gene correlation networks across brain regions
Authors: Mitra Sanga , B P Kailash , Srivatsan C R , Saikumar Naga Venkata , Philip Philge , Narayanan Manikandan 
Published: June 2023

AbstractBackgroundFunctional imaging has revealed how Alzheimer’s disease (AD) disrupts functional connectivity between brain regions, but the molecular basis of such changes has been less explored1. Genomic studies can reveal molecular/gene biomarkers in AD, but they have mostly been confined to within‐region analyses2. Here, we perform inter‐region analysis to explore how synchronized activities across brain regions are disrupted by gene‐pair rewiring in AD.MethodWe retrieved data on 264 AD and 372 control human post‐mortem RNA‐seq samples from Mount Sinai Brain Bank dataset for four brain regions: frontal pole (FP), superior temporal gyrus (STG), parahippocampal gyrus (PHG), and inferior frontal gyrus (IFG)3. Considering two brain regions at a time, we identified all pairs of genes across the two regions whose correlation strength is significantly altered in the AD group relative to the Control group4 (Fig. 1). The network of such differentially correlated (DC) genes provides information complementary to known differentially expressed genes in AD, and probably reflects cell‐intrinsic changes5 since we adjust for cell compositional effects.ResultWe found extensive DC gene pair rewiring in AD between pairs of brain regions, the most prominent being the coupling of PHG with other brain regions. Our analyses revealed that each brain region mostly uses a unique set of genes while interacting with other brain regions. Decomposing the bipartite DC network into gene modules revealed that certain gene modules affected in AD were enriched for synaptic signaling and ion transport pathways, whereas several others were enriched for AD GWAS (Genome‐wide Association Studies) signals. A module enriched for AD GWAS signal is also enriched for NF‐κβ signaling pathway, a key mediator of brain inflammation in AD. Beyond modules, we also identified individual genes such as ZKSCAN1 (Zinc Finger with KRAB And SCAN Domains) acting as a hub gene for most of the inter‐region comparisons and were enriched for AD GWAS signal.ConclusionThese findings provide novel insights into the network of pairwise gene relations underlying the functional connectivity between brain regions and highlights how disruption of different factors rewires this network in AD patients.1. Science, 1241‐4,2015.2. Genome Med., 104,2016.3. Sci Data., 180185,2018.4. BMC Res Notes., 54,2017.5. Bioinformatics, 1584‐91,2015.
Perplexity and its structural cerebral correlates: A promising marker for cognitive decline?
Authors: Herold Christina Josefa , Frankenberg Claudia , Abulimiti Ayimunishagu , Schultz Tanja , Kong Li , Schröder Johannes 
Published: June 2023

AbstractBackgroundRecent studies identified linguistic changes as a promising marker of early Alzheimer´s disease (AD) and mild cognitive impairment (MCI). Perplexity – i.e. a measure of content complexity and therefore predictability of speech – is considered as a predictive marker of AD and MCI in otherwise healthy elderly (Frankenberg et al., 2019). A higher score indicates a reduced predictability, i.e. for persons with high variability in their speech, the perplexity feature will have a very high value. However, the underlying brain structures are still unknown.MethodPerplexity was automatically examined in voice recordings of extensive autobiographical interviews obtained in 38 participants in their mid‐70ties (N = 26 cognitively healthy, N = 12 with MCI) from the Interdisciplinary Longitudinal Study on Adult Development and Aging (ILSE). Perplexities of 1‐gram and 2‐gram language models are investigated: The 1‐gram language model considers one word at a time, the 2‐gram language model considers each word in the context of its predecessor. Whole‐brain correlations between gray matter and perplexity were controlled for total intracranial volume, sex and education.ResultsAnalyses yielded significant positive correlations between measures of perplexity and right parahippocampal gyrus, right middle occipital gyrus, left middle temporal gyrus and right superior temporal gyrus (1 gram) as well as left precuneus and left anterior cingulate (2 gram).ConclusionThe correlation of perplexity with parahippocampal gyrus is paralleled by associations between this structure and autobiographical memory (Frankenberg et al., submitted). The superior temporal gyrus points to planum temporale, while the precuneus is involved in motor coordination and is connected to the anterior cingulate, which is associated with functions such as error detection and attention. The middle temporal gyrus is also considered to be language‐relevant in particular for lexical‐semantic and conceptual semantic aspects and the middle occipital gyrus is discussed as the Occipital Word Form Sensitive Area.
Genetic mapping of APP and amyloid‐β biology modulation by trisomy 21
Authors: Mumford Paige , Tosh Justin , Anderle Silvia , Gkanatsiou Eleni , Lau Gloria , Noy Sue , Cleverley Karen , Saito Takashi , Saido Takaomi C. , Yu Eugene Y. , Brinkmalm Gunnar , Portelius Erik , Blennow Kaj , Zetterberg Henrik , Tybulewicz Victor , Fisher Elizabeth , Wiseman Frances K 
Published: June 2023

AbstractBackgroundIndividuals who have Down syndrome frequently develop early onset Alzheimer’s disease, a neurodegenerative condition caused by the build‐up of aggregated amyloid‐β and tau proteins in the brain. Amyloid‐β is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer’s disease in these individuals.MethodsHere we use a combination of next‐generation mouse models of Down syndrome (Tc1, Dp3Tyb Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid‐β accumulation (AppNL‐F) to determine how chromosome 21 genes other than APP modulate APP/amyloid‐β in the brain when in three copies.ResultsWe demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid‐β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid‐β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2.ConclusionThus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid‐β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD‐DS compared to those who have familial AD caused by triplication of APP.