bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of peripheral immune system in a novel AppNL‐G‐F knock‐in mouse model of Alzheimer’s disease
Authors: Gera Ruchi , Mitra Sumonto , Tambaro Simone , Nilsson Per , Eriksdotter Maria 
Published: June 2023

AbstractBackgroundIncreasing epidemiological, clinical, and experimental evidence suggests that Alzheimer’s disease (AD) pathogenesis is closely associated with systemic abnormalities, including dynamic processes in the peripheral immune compartment and inflammation1,2,3. Recent reports in transgenic AD animal models propose a role of dysregulated peripheral immune system in memory impairment4,5. In this regard, the contribution of peripheral immune response in driving different pathological stages in AD is less understood. Therefore, utilizing a novel App knock‐in mouse model (AppNL‐G‐F) exhibiting robust Aβ pathology, neuroinflammation and memory impairment, we have explored the relation of Aβ pathology development in the brain with alterations in the peripheral immune compartment.MethodUsing flowcytometry, we characterized the AppNL‐G‐F mice at different stages of Aβ pathology (early‐plaque: 3‐month‐old; plaque + early memory impairment: 7‐month‐old; late stages: 12‐month‐old) and investigated the distribution and activation status of various peripheral immune cells in splenic primary cells.ResultAmong various immune cells from innate immunity including macrophages, natural killer and dendritic cells, there was a significant increase in macrophage number in AppNL‐G‐F mice. While percent distribution of B cells from adaptive immunity was reduced (as observed in AD patients2), no significant changes in total T cell distribution following 3, 7 and 12‐months of age compared to wild‐type controls was observed. B cells showed reduced activation examined by CD69 and PD‐L1 expression in 7 and 12‐months old AppNL‐G‐F mice. Among T cell subsets, CD4, CD8 and regulatory T (Treg) cell distribution in AppNL‐G‐F mice was comparable to control mice in all age groups. However, there was rise in follicular T helper (Tfh) cells at 3‐month of age, with altered activation molecule ICOS expression in AppNL‐G‐Fmice.ConclusionThese findings in AD mice model show a reduction in B cell and their activation status during aggressive Aβ plaque deposition in brain, reflecting their possible contribution in Aβ pathology reinforcing the importance of further investigation. Our data suggest a possible role of Tfh cell in early stage of Aβ pathology. An altered Tfh cell activation may answer the impaired protective antibody production from B cells reported in AD6,7. The observed increase in macrophages in the peripheral system during Aβ pathology development demands further investigation.
Evaluating a patient engagement program within a national research network
Authors: Bethell Jennifer , McGilton Katherine S , Snowball Ellen ,   Engagement of People with Lived Experience of Dementia (EPLED) Advisory Group
Published: June 2023

AbstractBackgroundThe Engagement of People with Lived Experience of Dementia (EPLED) is a program within the Canadian Consortium on Neurodegeneration in Aging (CCNA). The role of EPLED is to enable those with lived experience of dementia – persons with dementia and their care partners (i.e., friends, family and caregivers) – to be meaningfully and actively involved in the CCNA research process. The EPLED Advisory Group is composed of people with lived experience of dementia.MethodThe EPLED researchers, Advisory Group and program staff worked to develop an approach to evaluate EPLED activities. Evaluation will include capturing quantitative data on Advisory Group activities (e.g., number and nature of projects) as well as Advisory Group and CCNA perspectives on the engagement activity. Existing resources were used to identify key domains and Advisory Group members were invited to share their perspectives on the most relevant questions, including by voting on existing questions or suggesting their own. Ultimately, the Patient Engagement in Research Scale (PEIRS‐22) was selected to capture Advisory Group perspectives, but with two additional questions, from the full (37‐item) PEIRS and free‐text questions. EPLED also developed a short questionnaire for CCNA researchers to evaluate their experience working with Advisory Group members, including questions related to timing, objectives, engagement, collaboration and impact. Both questionnaires were transferred to Google Forms for online data collection.ResultWe will present the EPLED program evaluation plan and data from the first year of activities. We will describe the nature of the Advisory Group’s work as well as the perceptions from members and researchers.ConclusionPatient engagement in research is becoming more widespread and, for some research funding, an expectation. Our evaluation plan will be used to improve the EPLED program and plan future activities. Our results may also help other patient partners, researchers and research organisations to develop and implement their own activities.
Loss of apolipoprotein E exacerbates microglial and astrocyte reactivity to sustained systemic glucocerebrosidase inhibition
Authors: Connolly Kyle J , Hallett Penelope J , Isacson Ole 
Published: June 2023

AbstractBackgroundIncreased lipid storage is observed within the brains of patients with Alzheimer’s disease (AD). Genetic risk factors for AD involved in lipid processing include APOE, ABCA7 and TREM2. Lipid transport between neurons and glia is induced by mitochondrial stress and NMDA‐induced excitotoxicity in vitro and is dependent on glial apolipoprotein E (ApoE) expression. Therefore, this suggests that lipid transport between neurons and glia of the brain by ApoE and intracellular lipid processing are critical cellular adaptations to stress. This in turn suggests that insufficient ApoE activity may underpin the elevated lipid storage associated with neurodegenerative diseases.MethodTo determine whether ApoE function is required for cellular adaptation to increased lipid load relevant to dementia, 3‐month‐old WT and ApoE‐KO mice received daily intraperitoneal injections of the glucocerebrosidase inhibitor, CBE, for 18 d. Animals were sacrificed 1 d after the final dose and perfused with paraformaldehyde for immunohistochemistry, or were perfused with saline and dissected to isolate the cortex, hippocampus and substantia nigra for biochemical analysis by Western blot. Microglial and astrocyte reactivity to CBE were assessed by Iba1 and GFAP immunohistochemistry respectively.ResultMicroglial reactivity was greater in the dentate gyrus, substantia nigra and cortical layer V in ApoE‐KO mice after 18 d CBE, relative to WT. Loss of ApoE also elevated astrocyte reactivity in the dentate gyrus, substantia nigra and cortical layer V after 18 d CBE. Ongoing analyses into the molecular and cellular consequences of prolonged CBE include changes in lipid transport, tau phosphorylation, lysosome biogenesis, autophagy and proteostasis, to determine how loss of ApoE function may impact cellular adaptation to intracellular lipid formation resulting from sustained glucocerebrosidase inhibition.ConclusionThe exacerbated glial activation in ApoE‐KO animals receiving CBE suggests that ApoE expression and function may, in part, determine the capacity of neuron‐glia networks to overcome damaging stimuli. When ApoE function is insufficient, failed resolution of lipids may then lead to persistent damage and degeneration. Therefore, characterizing the consequences of limited lipid clearance on the adaptation to rising lipid load is highly relevant to understanding how failure to overcome increased lipid storage contributes to neurodegenerative processes in AD.
Methods in Prioritizing Pathways and Targets from Expression Data
Authors: Turkes Emir , Duff Karen E 
Published: June 2023

AbstractBackgroundExpression datasets, such as those from RNAseq and mass‐spec platforms, have been growing at an everincreasing rate and are relevant to a wide variety of diseases, however, it remains challenging to yield interpretable and actionable results. In this poster, we present novel computational methods that attempt to resolve this issues and demonstrate their use in several Alzheimer’s Disease datasets.MethodTwo publicaly available datasets were used for this analysis: a post‐mortem single‐nucleus RNAseq dataset from the entorhinal cortex of Alzheimer’s Disease and non‐demented donors (Leng et al., 2021, Nature Neuroscience) and a post‐mortem single‐soma RNAseq dataset from the prefrontal cortex of Alzheimer’s Disease donors where tangle‐bearing neurons were sorted prior to sequencing (Otero‐Garcia et al., 2020, bioRxiv). In brief, our method, which we have named GeneFunnel, firstly optimizes filtering steps and statistical correctness (such as pseudobulking) to yield robust gene set enrichment results. Gene set enrichment is then used to guide prioritization of differentially expressed genes using hierarchial clustering and graph theory, focusing especially on the overlap of genes between gene sets.ResultUsing several forms of visualization, we demonstrate how GeneFunnel can create a clear and succint overview of the processes involved in Alzheimer’s Disease. As the name implies, the results are made intuitively explorable, effectively facilitating a “funnel” that allows inspection at broad and narrow levels of depth.ConclusionWe show a novel approach to tackling large and complex expression datasets, demonstrating its utility in summarizing key molecular changes that take place in Alzheimer’s Disease.
The interaction between psychological resilience and perceived stress in relation to memory performance in middle‐aged adults
Authors: Franks Katherine H. , Buckley Rachel F. , Lim Yen Ying , Pase Matthew P. 
Published: June 2023

AbstractBackgroundHigh levels of perceived stress are associated with an increased risk of late‐life dementia. As such, it is important to investigate resources that might protect against the negative effects of stress, particularly in midlife when dementia is still preventable. One potential resource is an individual’s psychological resilience (i.e., their ability to cope with stress). The aim of this study was to investigate if the effect of perceived stress on memory depends on an individual’s level of resilience in a middle‐aged sample enriched for a family history of dementia.MethodParticipants (n = 1148) enrolled in the community‐based Healthy Brain Project aged 40‐71 (78% female, 61% with a family history of dementia) completed the Perceived Stress Scale, the Connor‐Davidson Resilience Scale, and the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning task. A two‐way ANCOVA was conducted to assess the interaction between perceived stress (low/high by median split) and psychological resilience (low/high by median split) on associative memory performance, while controlling for age and years of education. Simple main effects were Bonferroni adjusted.ResultThere was a statistically significant interaction between resilience and perceived stress on associative memory performance when controlling for age and education, F(1, 1142), 8.631, p = .003, partial h2 = .008. Bonferroni‐adjusted comparisons indicated that for individuals with low levels of resilience, associative memory was significantly poorer for those reporting high levels of stress relative to low levels of stress (mean difference = ‐0.31, 95% CI = ‐0.44 – ‐0.17, p < .001, Cohen’s d = 0.38). However, for individuals with high levels of resilience, associative memory performance between individuals reporting high and low levels of stress was comparable (mean difference = ‐0.01, 95% CI = ‐0.16 – 0.13, p = .857, Cohen’s d = 0.02).ConclusionIndividuals with low levels of resilience might be more susceptible to the negative effect of stress on memory than those with high levels of resilience. Further research is needed to explore whether boosting an individual’s resilience to stress can help mitigate cognitive decline and reduce dementia risk.
Prediction of multiple neuropathologic changes from features available during life
Authors: Phongpreecha Thanaphong , De Francesco Davide , Chang Alan , Thuraiappah Melan , Becker Martin , Ravindra Neal , Berson Eloise , Espinosa Camilo , Mataraso Samson , Godrich Dana , Beecham Gary W. , Aghaeepour Nima , Montine Thomas J. 
Published: June 2023

AbstractBackgroundNeuropathologic changes are central for both understanding of the patients’ brains and making the definitive diagnosis of dementia‐related diseases. However, many of them are only obtainable post‐mortem. To make this information available while an individual is still alive, this study developed machine learning models that predict neuropathologic changes based on features obtainable during life.MethodThe multi‐site post‐mortem data (n∼5000) was obtained from National Alzheimer’s Coordinating Center. A multitask long‐short term memory‐based neural network architecture was developed with custom loss to predict the 13 neuropathologic changes from features during life measured longitudinally. The performance of the model was evaluated using entire unseen sites as test sets. Evaluation metrics include area under receiver’s operating curve (AUROC) and area under precision recall curve (AUPRC).ResultThe model was able to predict Alzheimer’s Disease neuropathologic changes (ADNC) and any Alzheimer’s‐related pathologies, such as Braak score, with great sensitivity, specificity, and precision (for example AUROC = 0.85; AUPRC = 0.96 for ADNC). Apart from these, the model can also predict hippocampal sclerosis accurately (AUROC = 0.79; AUPRC = 0.80) and Lewy Body disease at higher precision than clinician’s diagnosis. Model interpretation shows patterns in neuropsychological tests that are predictive of pathologic changes. Additionally, model error analysis revealed factors, such as resilient case ratios, that explain variation in performance between sites.ConclusionPatterns of measurable features during life can be used by machine learning to predict ADNC, hippocampal sclerosis, and to lesser extent Lewy Body.
Variants near X‐Chromosome Genes NLGN4X and PTCHD1 are Significantly Associated with Alzheimer’s Disease Risk
Authors: Chung Jaeyoon , Sun Xinyu , Schmidt Michael A. , Song Yeunjoo E. , Grunin Michelle , Palmer Ellen L , Bush William S. , Naj Adam C. , Rajabli Farid , Hamilton‐Nelson Kara L. , Zhang Xiaoling , Leung Yuk Yee , Wang Li‐San , Mayeux Richard , Schellenberg Gerard D. , Vance Margaret A. , Haines Jonathan L. , Farrer Lindsay A. , Kunkle Brian W. , Martin Eden R. 
Published: June 2023

AbstractBackgroundGenome‐wide association studies (GWAS) for AD have identified numerous associated loci but have been focused only on the autosomes. We sought to identify novel AD‐associated genes on X‐Chromosome (X‐Chr).MethodWe evaluated the association of AD with X‐Chr variants in GWAS datasets assembled by the Alzheimer Disease Genetics Consortium including 26,322 non‐Hispanic White (NHW) individuals using logistic regression models with covariates for age, sex and principal components of ancestry. The number of independent SNPs in X‐Chr was calculated by linkage disequilibrium pruning yielding a study‐wide significance threshold of P<7.58×10−7. Genes near SNPs surpassing this threshold were further evaluated by expression quantitative trait locus (eQTL) in the BRAINEAC database and differential gene expression analyses using RNA‐seq data obtained from autopsied brains contained (GEO: GSE44772 and GSE33000). We also tested association of AD with missense or splicing variants with minor allele count (MAC)≥10 in the same genes using GENESIS and whole exome sequencing (WES) data obtained by the Alzheimer Disease Sequencing Project (ADSP) for 11,172 NHWs.ResultWe identified novel associations with variants near NLGN4X (rs34056759; minor allele frequency [MAF] = 0.15, OR = 1.15, P = 5.14×10−7) and PTCHD1 (rs5970663; MAF = 0.30, OR = 1.13, P = 8.26×10−7). The rs5970663 risk allele C was significantly associated with increased expression of PTCHD1 in the medulla region, and PTCHD1 expression was significantly higher in AD cases than in controls in the prefrontal cortex (P<2.1×10−8) and visual cortex (P<2.3×10−4). Rs34056759 was not associated with NLGN4X expression, but NLGN4X expression was significantly lower in AD cases compared to controls in the prefrontal cortex (P<8.7×10−7). A rare PTCHD1 variant (rs201933353; MAF = 0.001) was nominally associated with AD among 6,318 women (OR = 3.72, P = 0.06).ConclusionWe identified novel associations of AD with X‐Chr variants near NLGN4X and PTCHD1, loci that were previously associated with autism spectrum disorder. We plan to replicate, fine‐map, and annotate the candidate loci identified in this study using large whole genome sequencing ADSP datasets.
Functional brain networks reorganization in the absence of medial temporal lobe structures: an example of neuroplasticity
Authors: Peña‐Gomez Cleofé , Akinci Muge , Young Peter , Öhman Fredrik , Palpatzis Eleni , Studahl Marie , Arenaza‐Urquijo Eider M , Schöll Michael 
Published: June 2023

AbstractBackgroundMedial temporal lobe structures are particularly vulnerable in age‐related neurodegenerative diseases. Here, we investigated the brain reorganization that allows maintaining relatively normal global cognitive functioning in patients with herpes simplex encephalitis (HSE) – an infectious neurological disease ‐ with marked focal atrophy most pronounced in the medial temporal lobes, particularly the hippocampus. Using rs‐fMRI we (i) characterized the patterns of functional network organization, and (ii) compared the intra‐/interhemispheric functional connectivity (FC) within each patient.MethodA total of nine HSE patients were included (see Table 1), four of them were affected mainly in the left (LH) and five in the right (RH) hemisphere. The rs‐fMRI data were acquired after a long‐term follow‐up (median 16 years) of the disease and were preprocessed using the AFNI software. For each patient, using different brain parcellations, we computed the intra‐ and inter‐FC strength for each hemisphere separately, yielding four measures of intra‐FC
LH/RH
and inter‐FC
LH/RH
. We grouped the subjects according to their lesion‐side and their performance (low, high) in a memory task.ResultWe observed, regardless of the lesion side, a highly variable pattern of disrupted FC in each patient. Left‐lesioned patients showed high intra‐FCLH/RH particularly in the precuneus/posterior cingulate (PPC) and the angular gyrus while right‐lesioned patients exhibited a high inter‐FCRH in the medial prefrontal cortex (MPFC) and PPC regions. Both left and right‐lesioned showed decreased intra‐FCLH/RH in ventral medial temporal areas, more pronounced in the left‐lesioned patients (Figure1). Right‐lesioned individuals who showed a pattern of inter‐FC within the right MPF and PPC performed consistently higher on the memory task (percentiles > 50) (Figure2).ConclusionThe substantial HSE‐induced medial temporal lobe lesions induce a global network reorganization. However, the side of the lesion seems to determine a specific pattern of network reorganization that is associated with differential cognitive performance. Left‐lesioned patients exhibited high PPC intra‐ and inter‐FCLH/RH and low memory performance while the right‐lesioned exhibited a high inter‐FCRH on the PPC and MPFC and better memory performance. Left lesions may result in nonadaptive brain reorganizations, however, right lesions, when linked to prefrontal brain reorganizations, may result in cognitive benefits and therefore be adaptive.
2021 Annual Report of Japanese Brain Bank Network for Neuroscience Research
Authors: Murayama Shigeo , Saito Yuko , Takao Masaki , Kaneda Daita , Mihara Ban 
Published: June 2023

AbstractBackgroundJapanese Brain Bank Network for Neuroscience Research (JBBNNR) was established in 2001, whose reader is the Brain Bank for Aging Research (BBAR), the first and only Japanese Brain Bank dedicated for aging and dementia research.MethodBBAR recruited all the members of the Japanese Society of Neuropathology to establish JBBNNR, funded by MEXT in 2001, on the following four conditions: open resource, to organize brain donation system, to share quality control including neuropathological method and to combine clinical longitudinal studies like US ADNI. National Center of Neurology and Psychiatry (NCNP), Mihara Memorial Hospital and Fukushimura Hospital joined JBBNNR. In 2020, Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders (BBNNPD) joined JBBNNR. JBBNNR was established in United Graduate Shool of Child Development, Osaka University and was the first brain bank system in all the universities of Japan.ResultIn 2021, the pandemic of COVID‐19 seriously influenced recovery of postmortem brains via dramatic decrease of autopsy. JBBNNR promoted brain donation and began effort to include legal autopsy for Japanese equivalent of suicide bank and autism brain net in US. The main barrier resides in cultural respect of suicide in Japan, which makes it difficult to obtain the deceased first kin of relatives' consent for brain donation. The solid public support system for autism promised long life without accident and makes it difficult to recover autism brains through forensic pathology. A goog news is that BBNNPD proposed cloud funding in Osaka for the research of neurodevelopmental disorders and intractable neurological disorders and successfuly received donation of ten million yen. The main target of JBBNNR is Alzheimer disease and contributed clinical trials of amyloid pet in Japan. JBBNNR is based on full autopsy and reported that one third of geriatric population contained Lewy body pathology in the body. BBAR received the best reserch presentation award from the Japanese Society of Dementia Research about correlationg of in vivo PIB PET and postmortem Abeta deposition with shor interval.ConclusionJBBNNR continued to contribute neuroscience research, focused AD and dementia, in Japan.