bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperbaric oxygen ameliorates cognitive impairment in patients with Alzheimer’s disease and amnestic mild cognitive impairment
Authors: Le Weidong 
Published: December 2020

AbstractBackgroundIt is reported that environmental factors such as hypoxia could contribute to the pathogenesis of Alzheimer’s disease (AD). Therapeutics like hyperbaric oxygen treatment which improves tissue oxygen supply and ameliorates hypoxic conditions in the brain may be a strategy for AD and amnestic mild cognitive impairment (aMCI) treatment. The present work aims to investigate the potential therapeutic effect of hyperbaric oxygen treatment in patients with AD and aMCI.MethodWe included 42 AD and 11 aMCI patients in this study. All participants were continuously treated with hyperbaric oxygen treatment once daily for 20 days and assessed by neuropsychiatric assessments before and at 1, 3, and 6 months after the hyperbaric oxygen treatment. We also applied fluorodeoxyglucose positron emission tomography (FDG‐PET) in some of the patients.ResultHyperbaric oxygen treatment could improve the global cognitive functions, especially visuospatial and executive functions, language and abstract thinking abilities at 1 month after treatment in AD patients and improved the memory of aMCI patients in 1, 3, and 6 months after treatment. The ADL scores were improved in 1, 3, and 6 months after treatment in AD patients. Hyperbaric oxygen treatment also ameliorated the reduced brain glucose metabolism in AD and aMCI patients.ConclusionBased on the previous studies and our recent findings, hyperbaric oxygen treatment may be a potential therapeutic and preventive strategy for AD and aMCI.
Hearing loss and microstructural integrity of the brain in a dementia‐free older population
Authors: Croll Pauline H , Vernooij Meike W , Reid Robert I , Goedegebure André , Power Melinda C , Rigters Stephanie C , Sharrett A Richey , de Jong Robert J Baatenburg , Mosley Thomas H , de Groot Marius , Lin Frank R , Deal Jennifer A 
Published: December 2020

AbstractBackgroundRecently, hearing loss has been identified as a promising modifiable risk factor for dementia. Several hypotheses explaining a potential underlying pathway have been proposed, including the sensory deprivation hypothesis, describing a direct causal relationship in which hearing loss leads to neuroplastic changes in the brain. Indeed, hearing loss has been associated with smaller macrostructural brain volumes, which is believed to at least partly explain the association between hearing loss and neurodegenerative disease. However, microstructural changes precede macrostructural changes. Therefore, we aimed to assess the association between hearing loss and microstructural integrity of the brain.Methods1,086 dementia‐free older adults from the Atherosclerosis Risk in Communities (ARIC) study (mean age = 75.2 [SD: 4.9], 61.4% female) underwent hearing assessment (2016‐2017) and magnetic resonance imaging (MRI) of the brain (2011‐2013). Hearing was assessed with pure‐tone audiometry. Microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD)) of multiple brain regions was determined with diffusion tensor imaging (DTI). Multivariable linear regression models were used to investigate the association between hearing loss and microstructural integrity of the lobes, temporal lobe gyri, medial temporal lobe structures and white matter (WM) tracts, adjusting for relevant confounders.ResultHearing loss was associated with lower WM microstructural integrity in the temporal lobe (difference in SD FA for moderate/severe hearing loss as compared to normal hearing: ‐0.19 [95% CI: ‐0.35, ‐0.03]; and difference in SD MD for moderate/severe hearing loss as compared to normal hearing: 0.15 [95% CI: 0.01, 0.28]). Hearing loss was associated with lower gray matter (GM) microstructure of the hippocampus, but not the amygdala. Moreover, hearing loss was associated with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus (Figure 1).ConclusionOur results demonstrate that age‐related hearing loss is associated with lower WM microstructural integrity in the temporal lobe, the limbic tracts and the uncinate fasciculus and lower GM microstructure in the hippocampus. These associations suggest that poorer hearing may affect brain regions that are important for different cognitive processes. However, the results should be interpreted with caution as this study is of a cross‐sectional design.
Biological substrates of cortical atrophy in prodromal AD: A CSF proteomic study
Authors: Ekblad Laura L. , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2020

AbstractBackgroundBrain atrophy is a characteristic feature of Alzheimer´s disease (AD). Atrophy typically begins in the medial temporal regions and is closely related to cognitive decline. The biological processes that associate with or possibly lead to regional cerebral atrophy are largely unexplored. We used a cerebrospinal fluid (CSF) proteomic approach to study which biological processes are associated with cortical atrophy in prodromal AD.MethodProdromal AD individuals based on abnormal CSF beta‐amyloid were selected from ADNI when they had structural MRI and CSF proteomic data (measured with MRM and RBM). Correlations between 217 CSF proteins and cortical thickness of 34 cortical regions (averaged over the left and right hemispheres) were analyzed with linear models. We used hierarchical clustering to identify clusters of brain regions that showed similar CSF protein correlations. ClueGO enrichment analysis was used to identify biological processes associated with proteins that correlated with atrophy.ResultWe included 104 individuals (37.5% female; mean age 74.5±7.2 years). In total 150 proteins showed associations with cortical thickness in at least one brain region (p<0.05). We identified 4 clusters of brain regions that showed similar proteomic correlations with atrophy (Figure 1). Cluster 1 included the medial temporal, medial orbitofrontal and superior temporal regions. In these regions thinner cortex was associated with lower levels of proteins involved in the beta‐amyloid metabolic process and synaptic plasticity. Cluster 2 included dorsolateral frontal regions and the isthmus cingulate, and lower cortical thickness was associated with higher levels of proteins that reflect inflammatory processes and blood‐brain barrier disruption (Dayon et al. J Proteome Res. 2019;18:1162‐1174). Cluster 3 included the precuneus, superior and caudal middle frontal and superior parietal regions and the paracentral and postcentral gyri. Cortical thinning in Cluster 3 was associated with higher levels of proteins that associated with embryogenic hemopoiesis. Cluster 4 included regions in which thinning was not associated with CSF proteins.ConclusionIn prodromal AD, regional cortical atrophy is associated with disruptions in distinct biological processes depending on the region involved. This suggests that treatment may need to consider a combination of targets in order to prevent atrophy, and eventually cognitive decline.
Platelet‐derived growth factor receptor‐beta as a potential CSF biomarker for Alzheimer’s disease
Authors: Kuiperij H. Bea , de Kort Anna M. , Kersten Iris , Versleijen Alexandra A.M. , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Claassen Jurgen A.H.R. , Verbeek Marcel M. 
Published: December 2020

AbstractBackgroundThere is a lack of biomarkers for the early detection of Alzheimer’s disease (AD). Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid‐β (Aβ) in the cerebral vasculature, is commonly found in AD. Platelet‐derived growth factor receptor‐β (PDGFRβ) is expressed by pericytes and since blood‐brain barrier (BBB) dysfunction is associated with pericyte degeneration, release of PDGFRβ protein may be a biomarker for BBB dysfunction, that is expected in CAA. Indeed, it has recently been described that PDGFRβ levels are elevated in cerebrospinal fluid (CSF) from patients with mild cognitive impairment (MCI) as compared to controls1. The aim of our study was to investigate the diagnostic and discriminative value of PDGFRβ in CSF in patients at various clinical stages of AD and in patients with CAA.MethodCSF PDGFRβ, Aβ42, total tau (t‐tau) and phosphorylated tau (p‐tau) levels were quantified by ELISA. Cohorts of controls (n=47), CAA patients (n=27) and AD patients (n=59; 19 patients with MCI (clinical dementia rating (CDR) = 0.5), 28 patients with CDR 1.0 and 12 patients with a CDR of ≥ 2.0) were studied.ResultCSF PDGFRβ levels were similar in controls, AD and CAA patients. Moreover, PDGFRβ levels were similar in patients at the various clinical stages of AD. PDGFRβ levels also did not correlate with blood‐CSF barrier dysfunction (i.e. elevated albumin ratio). We observed a strong correlation of CSF PDGFRβ levels with t‐tau and p‐tau levels, the degree of which was dependent on the CDR score. Interestingly, CSF PDGFRβ levels were significantly elevated in a selection of MCI/AD patients with an AD‐positive CSF biomarker profile (A+T+) as compared to controls with a completely normal profile of AD biomarkers (A‐T‐N‐).ConclusionWe could neither confirm previously reported elevated CSF PDGFRβ levels in MCI patients1, nor did we find elevated PDGFRβ levels in CAA patients. Our results suggest that CSF PDGFRβ levels are not useful as marker of BBB integrity, but instead may, as previously reported, be associated with AD (tau) pathology2. References: 1Nation et al., Nat Med. 2019;25(2):270‐276; 2Miners et al., Alzheimers Res Ther. 2019;11(1):81.
Characterization of DNA methylomic signatures in induced pluripotent stem cells during neuronal differentiation
Authors: Imm Jennifer L. 
Published: December 2020

AbstractBackgroundIn development, inducing pluripotency and differentiation into different cell types results in global epigenetic changes, although the extent this occurs in induced pluripotent stem cell (iPSC)‐based neuronal models has not been extensively characterized.MethodHuman fibroblast cells were reprogrammed using lentiviral transfection. The resulting iPSC colonies were expanded, differentiated and collected at three different time points: day0 (iPSCs), day16 (neuronal progenitor cells), day37 and day58 (mature neurons). DNA methylation was assessed using the Illumina EPIC array. Using WGCNA, trajectory inference modelling and pathway analysis we identified loci undergoing dynamic changes during differentiation and the pathways these loci are associated with.ResultThis study has identified methylomic variation associated with neuronal differentiation and maturation. We identified 5,866 Bonferroni‐significant loci during differentiation using lineage modelling and noted that these loci are involved in pathways associated with head development, transcriptional regulation and cellular signalling. A gene‐gene interaction network analysis identified 50 densely connected genes that are influential in the differentiation of neurons, with STAT3 being the gene with the highest connectivity. Finally, we demonstrated that despite being functionally mature these iPSC‐derived neurons have a fetal epigenome.ConclusionWe have shown that there are large epigenetic changes occurring throughout neuronal differentiation. These changes are within pathways that are key to neuronal development. Alongside this we have also identified an epigenetic trajectory signature associated with maturation and shown that neurons derived from iPSCs have a fetal epigenome.
Polygenic‐wide analysis to assess the impact of genetic risk profiles on brain morphometry in the ALFA study
Authors: Vilor‐Tejedor Natalia , Guigó Roderic , Operto Greg , Crous‐Bou Marta , Cacciaglia Raffaele , Falcon Carles , Arenaza‐Urquijo Eider M , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Gispert Juan Domingo 
Published: December 2020

AbstractBackgroundNeurodegenerative diseases are associated with progressive neuronal vulnerability and loss of function, along with an accelerated brain atrophy, which is partly influenced by multiple genetic factors. Polygenic risk scores (PRSs) are used for both identifying the genetic architecture of complex diseases and predict disease genetic risk (GR), as well as testing its shared genetic architecture. In this study we investigated whether a genetic predisposition to neurodegenerative and related complex diseases were associated with brain morphometry in a sample of cognitively unimpaired individuals of the ALFA cohort.MethodA total of 479 participants with available genotype and neuroimaging data were included. PRSs were calculated from the most recent genome‐wide association meta‐analyses for neurodegenerative diseases (Alzheimer’s disease (AD), parkinson disease), related complex diseases (stroke, hypertension, hypercholesterolemia, diabetes, depression, cerebrovascular disease (CV)), and susceptibility to AD‐core biomarkers (p‐tau and amyloid Aβ‐42). Association analyses included measures of brain morphometry as outcomes. PRS were standardized for easy interpretation. Associations were estimated using linear regression models. All models were adjusted for age, sex, education, APOE‐ϵ4 status, and total intracranial volume.ResultPreliminary results suggested increased PRS average of AD, tau and Aβ42 levels, indicating higher genetic risk for ALFA participants [Figure 1]. In addition, we found strong positive correlation patterns between GR of hypertension with diabetes, GR of cholesterol with hypertension and diabetes, and GR of depression with diabetes, hypertension and cholesterol [Figure 2]. Furthermore, the most remarkable results suggested evidence of association between increased risk of cholesterolemia and reduced volumes of left accumbens area, increased risk of CV and reduced volumes of thalamus proper, as well as increased risk of tau and reduced volumes of right thalamus proper and right cerebellum cortex [see Figure 3 for further results].ConclusionWe identified strong evidence that genetic liability of related cardiovascular diseases and AD‐core biomarkers influences brain morphology in ALFA. In addition, across all diseases, ALFA participants showed increased genetic risk on AD, and AD‐core biomarkers. In further analyses, we will assess the relationship between neuroanatomical differences in the whole brain and PRSs using voxel‐based morphometry analyses.
Contribution of Alzheimer’s disease risk genes in the maintenance of endolysosomal transport regulation
Authors: Bretou Marine , Sannerud Ragna , Vermeire Wendy , Demedts David , Annaert Wim 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia of which the incidence increases with age. No cures are available yet, urging to explore new strategies for the identification of pathways that can be targeted therapeutically. Research in AD has been majorly driven by studying familial AD (FAD)‐associated mutations in the APP and PSEN genes, albeit they represent only a minor fraction of all cases. GWAS studies have identified ≈30 late‐onset AD (LOAD) susceptibility loci that, when functionally clustered, are directly or indirectly linked to cellular trafficking routes and functioning. These include genes linked to cholesterol metabolism (e.g. APOE4, ABCA7, INPP5D), endocytic transport regulation (e.g. BIN1, CD2AP, PICALM, SORL1) and lysosomal processes (e.g. GRN, PLD3). The genetic findings concur with the appearance of endolysosomal abnormalities at preclinical stages, before the appearance of senile plaques and tangles.MethodTo investigate the role of LOAD risk factors involved endosomal transport regulation, we generated knock‐out (KO), and their corresponding rescued cell lines for several proteins including PSENs, PICALM and PLD3 and this in fibroblasts and neuronal SHS5Y5Y cells. These are now subjected to a comparative analysis of the endolysosomal pathway and lysosomal function.ResultPSENdKO cells present with enlarged late endosomes/lysosomes that (i) display an increased co‐localization with early endosomal markers, (ii) accumulate various lipids as shown by lipidome profiling of isolated organelles, and (iii) accumulate various cargoes and adaptors such as the retromer subunit VPS35. These aberrant accumulations could be corrected by the re‐expression of catalytic active and inactive human PSEN1, indicating that a γ‐secretase‐independent role of PSEN1 is partially connected to recycling. Interestingly, activation of recycling could significantly alleviate endolysosomal defects observed in PSEN KO cells. Ongoing analysis of LOAD risk genes shows both similar as well as distinct endolysosomal defects underscoring that a possible common endosomal deregulations may originate from different upstream mechanisms.ConclusionTogether, these observations are shedding light on the potential of modulating/restoring endosomal transport regulation as a strategy to alleviate observed early endolysosomal dysfunctions at preclinical stages of AD pathogenesis.
Resilience monitor for informal caregivers for people with dementia (REMIND): Digital monitoring of informal caregivers’ well‐being to prevent crises
Authors: Oostra Dorien L. , Nieuwboer Minke S. , Rikkert Marcel G.M. Olde , Perry Marieke 
Published: December 2020

AbstractBackgroundThe number of people with dementia living at home is likely to increase, resulting in a growing societal dependency on informal care. Informal caregiving causes a considerable burden on caregivers’ wellbeing, both physical and mental. A decrease in caregivers’ wellbeing is often a direct reason for crisis admission of the person with dementia. Close monitoring of wellbeing and resilience of caregivers followed by early intervening by case managers may prevent crisis. Our aim is to develop a user‐friendly digital monitor to assess wellbeing and resilience of caregivers to enable case managers to provide timely support and prevent crises.MethodA human centered design method was used. To identify wishes and needs, develop ideas for the monitor and test first visual prototypes, focus groups with end users and experts in the field of primary dementia care took place. End users were informal caregivers and professionals from different disciplines. Experts were researchers, clinicians, innovation experts and application designers. The 3‐month pilot study will include caregivers and case managers and consists of monitoring wellbeing and resilience weekly by a set of questions. Intervention delivery and acceptability will be assessed together with changes in number of crisis and caregiver’s perseverance time.ResultThree focus groups with end user and multiple expert sessions took place. Wishes, needs and functionalities were identified during the first two focus group meetings. To detect deterioration of caregivers’ wellbeing earlier, an application connected to a dashboard with an alert system for case managers is desired. To assess wellbeing, questions were reviewed during the third meeting covering the topics: social support, reciprocity, burden/competence, mood, own activities, small crises, person with dementia. Caregivers indicated they want to fill in approximately seven questions per week. Additionally, concept screens of the application and dashboard were discussed. Preliminary results of the pilot study will include adherence, user satisfaction and usability.ConclusionThis methodological approach will result in a product that best meets the needs and wishes of caregivers and case managers in order to prevent crises. The pilot study will provide insight into the possible effectiveness and usefulness of this product in practice.
Neurotoxicity and hyperphosphorylation of tau protein induced by the amyloid peptide oligomers involve different glutamate dependent and independent mechanisms
Authors: Henriques Alexandre , Rouvière Laura , Farrugia Clémence , Poindron Philippe , Callizot Noelle 
Published: December 2020

AbstractBackgroundAlzheimer’s disease is characterized by the extracellular accumulation of senile plaques composed of amyloid beta and the intracellular deposition of neurofibrillary tangles composed of hyperphosphorylated tau (Tp). Aβ oligomers (AβO) induced sequential damages starting with synapses loss, followed by the neurite network disorganization and finally the neuronal death. In this study, we deeply investigated the role of glutamate and its receptors (mGluR5 and NMDARs) in the AβO neurotoxicity and in the Tp.MethodUsing primary cultures of rat embryonic cortical neurons, the AβO toxicity was investigated in presence or absence of glutamate receptor antagonists (MPEP, Ifenprodil, MK801, memantine...). The AβO effects on the glutamate release and on the Ca2+ flux were studied in presence or absence of BAPTA in the medium. In addition, the AβO effect on the hyperphosphorylation of Tau was studied. Different sites of hyperphosphorylation were investigated (AT100, AT8 and Thr231 involving the DAPK1 and GSK3β).ResultWe showed that 5 min after AβO application, a large release of glutamate was seen in the extracellular medium. This release was immediately followed by a Ca2+ entrance in the neurons. In absence of extracellular Ca2+, the caspase‐3 activation was abolished as well as the neuronal death. Similarly, in presence of NMDAR or mGluR5 antagonists, the neuronal death was abolished, by contrast, Tau hyperphosphorylation and aggregation was still observed.ConclusionAltogether, these findings showed the crucial role of glutamate and Ca2+ in the AβO acute neuronal death, and demonstrated that the effects on Tp might not involve the NMDAR and the mGluR5.