bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive and biological characteristics of stage 2 of AD in the clinical multicenter DELCODE Study
Authors: Jessen Frank , Boecker Henning , Buerger Katharina , Heneka Michael T. , Laske Christoph , Peters Oliver , Perneczky Robert , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan J. , Wiltfang Jens , Wagner Michael , Düzel Emrah 
Published: December 2020

AbstractBackgroundStage 2 of Alzheimer’s disease holds particular promise for early treatment, because of largely preserved cognitive functioning. Also individuals at stage 2 may contact the medical system due to subjective cognitive (SCD) and potentially mild behavioral symptoms. Current research focuses on the refined symptomatic and biological characterization of stage 2 and the longitudinal cognitive course from stage 2 onwards.MethodThe DZNE (German Center for Neurodegenerative Diseases)‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE) is a memory clinic based project, which enrolled 1078 participants of which 420 were patients with SCD. Extended clinical, cognitive, biomarker and neuroimaging assessments at baseline were performed. Annual follow‐up is ongoing with some having reached the fifth year of observation.ResultParticipants with SCD showed lower concentration of Aß42 in the cerebrospinal fluid and a higher rate of cut‐off‐based amyloid‐positivity. Baseline clinical and biological data, including magnetic resonance imaging (MRI), as well as longitudinal cognitive data of participants fulfilling criteria of stage 2 (SCD and amyloid positivity) will be presented in comparison with data of control subjects, amyloid negative SCD participants, participants with mild cognitive impairment (MCI) and with mild AD dementia.ConclusionStage 2 of AD may be a future target for early treatment. SCD may serve as a clinical indicator of stage 2. DELCODE and other memory clinic‐based studies provide the basis to understand the potential usefulness of stage 2 in clinical trials and clinical practice in the future.
Hyperexcitable PV interneurons render hippocampal microcircuitry vulnerable to amyloid beta
Authors: Hijazi Sara , Heistek Tim , Mansvelder Huibert D. , Smit August B. , van Kesteren Ronald E. 
Published: December 2020

AbstractBackgroundHippocampal Parvalbumin (PV) neurons are GABAergic inhibitory interneurons that provide feedback and feedforward inhibition. They control hippocampal local circuitry and are essential for spatial learning and memory. Accordingly, their dysfunction has been associated with Alzheimer’s disease (AD). Previously, we showed that an early amyloid‐beta dependent PV hyperexcitability is causally involved in hippocampal circuit dysfunction and cognitive impairment in a mouse model of AD. Here, we investigate the short‐ and long‐term effects of PV hyperexcitability on hippocampal function and test whether PV neuron hyperexcitability can render hippocampal circuits vulnerable to amyloid beta.MethodWe use chemogenetics (hM3Dq‐activating receptor with clozapine‐N‐oxide) in order to increase PV neuron activity for three weeks. We then train the mice in the Morris water maze (MWM) in order to asses hippocampus‐dependent spatial memory. Finally, using whole‐cell patch‐clamp recordings, we investigate PV and pyramidal neuron excitability and synaptic transmission in the hippocampus.ResultWe found that prolonged activation of PV neurons disrupts synaptic transmission and causes spatial memory deficits on the short‐term, while on the long‐term, natural compensatory mechanisms restore synaptic transmission and spatial memory. A single low‐dose of amyloid‐beta disrupts long‐term restoration of hippocampal synaptic transmission when PV neurons are hyperexcitable. Specifically, under these conditions, amyloid‐beta impairs PV neuron function, resulting in significant spatial memory deficits.ConclusionTaken together, our data show that an induced hyperexcitablity state of PV neurons render hippocampal circuitry vulnerable to amyloid‐beta.
General practitioners’ opinion on early and pre‐dementia diagnosis of AD: A MOPEAD project survey in five European countries
Authors: Sannemann Lena , Müller Theresa , Waterink Lisa , Zwan Marissa D. , Wimo Anders , Stomrud Erik , Pino Susana , Espinosa Jordi Arrufat , Rodriguez‐Gomez Octavio , Benaque Alba , Bon Jaka , Dron Amanda , Ferreira Daniel , Johansson Gunilla , Dumas Annette , Georges Jean , Kramberger Milica G. , Visser Pieter Jelle , Winblad Bengt , Campo Laura , Boada Mercè , Jessen Frank ,   the MOPEAD Consortium
Published: December 2020

AbstractBackgroundOver the last decade, research efforts have facilitated early detection of dementia and underlying diseases, such as Alzheimer disease (AD). There is growing evidence for the benefits of early diagnosis, including access to education, available treatment and support. On the other hand, the lack of a cure and the fear to stigmatize the patient are among the arguments that speak against early disclosure of a diagnosis. General Practitioners (GPs) are often the first contact person when cognitive changes arrive, and they play a key role in early identification of the disease. Based on the experiences working with GPs as part of the multinational “Models of Patient Engagement for Alzheimer's Disease” (MOPEAD) project, an EU‐funded public‐private study within the Innovative Medicines Initiative (IMI‐2) research agenda, we aimed to assess the current attitude of GPs towards early and pre‐dementia diagnosis for AD at the stage of mild cognitive impairment (MCI) or very mild dementia.MethodWe designed a survey to measure the current attitude of GPs towards early and pre‐dementia diagnosis of AD at the MOPEAD sites in five European countries (Germany, Slovenia, Spain, Sweden, and the Netherlands). The questionnaire covered several topics, including attitude towards early diagnosis, diagnostic procedures, resources and opinion on present and future treatment options. Chi‐square tests were carried out to analyze differences among countries.Result343 GPs completed the survey. In total, 74% of GPs indicated that they considered an early diagnosis of value. However, only 44% of GPs felt confident in handling the diagnostic procedures for very early dementia and MCI. Currently available pharmacological treatments were mostly regarded as having low benefit, while 68% considered non‐pharmacological treatment options as “beneficial and not sufficiently available”. There were country‐specific differences in the GPs’ perception of monetary resources (X
2(4)=117.26, p < .001) and time (X
2(4)=14.84, p > .01) available for the patient.ConclusionOur findings provide an up‐to‐date overview on GPs’ opinion towards early and pre‐dementia diagnosis in five European countries. We show that the majority of GPs considers an early diagnosis beneficial, yet they are faced with country‐specific challenges that can contribute to delayed or missed diagnosis.
Association between social class and cognitive health outcomes in older adults: Systematic review and meta‐analysis of longitudinal studies
Authors: Bodryzlova Yuliya , Belanger Emmanuelle , Moullec Gregory 
Published: December 2020

AbstractBackgroundBeing born into a given social class still predetermines many aspects of a person’s cognitive biography. People of higher social class have better access to education; to prestigious creative and morally rewarding jobs; and to secure income. Hence, they have better access to two most powerful dementia‐protective factors: life‐long cognitive stimulation and lower level of stress. In this work, we synthetize the association between social class and cognitive health outcomes.MethodSystematic review and meta‐analysis were conducted. Inclusion criteria were community‐dwelling people age 65 and older; social class as an exposure; dementia, Alzheimer’s disease or cognitive impairment as outcomes; longitudinal observational study as the study design. MEDLINE and Psychinfo databases were used between 01/01/1979 and 07/04/2019. In selected studies, fixed and random effects and homogeneity of effects were calculated. Sensitivity analyses, subgroup analyses and meta‐regression were used to examine sources of heterogeneity and to find possible mediators.Result998 abstracts were screened; 38 full‐text articles selected; 8 articles retained in analysis, 3 articles were found in references and 1 article was excluded because it described the same population/outcome. 54 dyads “exposure/outcome” were extracted. Individual (education, income, occupation) and group (neighbourhood) variables were used as indicators of social class. Regardless social class indicator, the pooled RR for dementia/cognitive impairment was 2.45 for fixed effect and 2.18 (95%CI: 2.03 to 2.34) for random effect with I2 heterogeneity of 78%. In sub‐analysis of different social class indicators, the association was strong and homogeneous for income (pooled RR for random effect: 2.07 (95%CI: 1.83 to 2.34), I2: 45%, occupation (RR: 2.53 (95%CI: 2.34 to 2.86), I2=14%) and neighbourhoods (RR: 2.47 (95%CI: 2.33 to2.61), I2=0%). Although education (RR: 2.08 (95%CI: 1.82 to 2.38) had an overall significant association with the cognitive health outcomes, there was a large heterogeneity in the effect (I2=78%).ConclusionThere is a strong and consistent association between social class and the risk of dementia/cognitive impairment in advanced age. Growing inequality in financial security, favorable workplace conditions and healthy local environments aggravate existing challenges of dementia. Our findings can give insight to policy makers targeting healthy cognitive aging in populations.
Network abnormalities and interneuron dysfunction in Alzheimer’s disease
Authors: Palop Jorge J. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) results in deterioration of cognitive functions and abnormal patterns of neuronal network activity, including network hyperactivity and altered oscillatory rhythms, but the underlying cellular and circuit mechanisms are poorly understood.MethodsThe brain relies on oscillatory rhythms, generated by inhibitory interneurons, to precisely time neuronal firing required for circuit functions.ResultsIn this session, we will discuss our recent findings suggesting that interneuron impairment critically contributes to network hyperactivity, altered oscillatory rhythms and cognitive decline in multiple mouse models of AD. We found that oscillatory rhythms reflect behavioural states and strongly modulate network hypersynchrony in mouse models of AD, including including J20 and APP/PS1 mice. Specifically, pathological network hypersynchrony emerges during resting states characterized by decreased gamma oscillatory power and aberrant increases of low‐frequency (12‐20 Hz) oscillatory power. Inhibitory interneuron deficits in AD mouse models are in part mediated by decreased levels of the interneuron‐predominant voltage‐gated sodium channel Nav1.1 subunit. Importantly, restoring Nav1.1 levels and interneuron function by Nav1.1BAC overexpression or interneuron transplants improves interneuron–dependent gamma oscillatory activity, theta‐gamma phase‐amplitude coupling, survival, circadian rhythms and cognitive performance in J20 and APP/PS1 mice, revealing key functional roles for Nav1.1 and inhibitory interneurons. We will also discuss the specific contributions of interneuron cell types such as fast‐spiking (FS, PV) and non‐fast spiking (NFS, SOM) interneurons to generate gamma oscillatory activity and the underlying circuits and cellular mechanisms responsible for altered gamma oscillations in AD mice by optogenetic approaches and multi‐unit and local field potential (LFP) recordings in vivo. Our results suggest that distinct interneurons cell types such as PV and SOM interneurons synergistically cooperate to generate gamma oscillation in vivo and that J20 mice have cell‐type specific functional impairments in this circuit that lead to impaired oscillatory activity. Finally, we will also discuss our translational efforts identifying small molecule Nav1.1 enhancers to increase interneuron function.ConclusionOur results highlight the potential therapeutic benefit of restoring inhibitory interneuron function and oscillatory rhythms for cognitive functions and that targeting network dysfunction represents an attractive and complementary therapeutic approach.
The association between tau aggregation and microglia in frontotemporal lobar dementia
Authors: Hartnell Iain James , Blum David , Nicoll James A.R. , Dorothee Guillaume , Boche Delphine 
Published: December 2020

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) describes a neurodegenerative disorder caused by protein accumulation in the brain, with the most common form due to aggregated Tau (FTLD‐tau). A potential role for neuroinflammation in FTLD has been highlighted by the discovery of genetic risk variants related to innate/adaptive immunity. Furthermore, studies have shown increased microglial and astrocyte activation together with T cell infiltration in the brain of a mouse tauopathy model (THY‐Tau22).MethodsTo test the possible neuro‐immune interactions in human FTLD‐tau, we obtained FFPE brain tissue from 12 FTLD‐MAPT, 33 Pick’s Disease (PiD) and 45 Progressive Supranuclear Palsy (PSP) patients, as well as 55 controls. Using immunohistochemistry we assessed the tau pathology across diseases using antibodies against several sites of tau phosphorylation in association with phenotypic markers of microglia and T cells.ResultsOur results show that PiD, PSP and FTLD‐MAPT patients had significantly higher phosphorylated tau protein loads (AT8: p<0.001 for all, AT100: p<0.001 PiD & FTLD‐MAPT, p = 0.009 PSP) compared to controls. We also observed a significant correlation between AT8 and AT100 in all but control groups. Whilst no significant changes were seen between groups in microglial markers (Iba1, CD68 and HLA‐DR), significant associations were seen between AT8 and CD68 in control (r=0.389, p<0.004) and PSP cases (r=0.422, p<0.004), with associations between AT100 and CD68 in PiD (r=0.547, p=0.001) and FTLD‐MAPT (r=0.762, p=0.005).ConclusionThese findings support the involvement of microglia in FTLD, but additional immunophenotyping is necessary for further defining their role in the disease pathogenesis.
The viral protein corona directs viral pathogenesis and amyloid aggregation
Authors: Ezzat Kariem , Malm Tarja , Gustafsson Oskar , Lindén Anders , Andaloussi Samir E.L. 
Published: December 2020

AbstractBackgroundViruses rely on the intracellular host machinery for replication, production of viral proteins and assembly. However, outside cells, as nanosized obligate intracellular pathogens, viruses share many biophysical properties with nanoparticles. Based on this biophysical equivalence, we hypothesized that viruses accumulate a host‐derived protein corona layer in extracellular environments similar to nanoparticles. Also, like nanoparticles, viruses should be able to function as nanosurface catalysts that enable accelerated amyloid protein aggregation extracellularly.MethodWe analyze the protein corona of respiratory syncytial virus (RSV) and herpes simplex virus 1 (HSV‐1) in different biological fluids including human plasma, human bronchoalveolar lavage fluid, non‐human primate plasma, and fetal bovine serum using proteomics, electron microscopy, infectivity and dendritic cell activation assays. In addition, we study the effect of RSV and HSV‐1 on the kinetics of amyloid aggregation of amylodogenic peptides such as amyloid‐beta (Aβ42) peptide, which is the major constituent of amyloid plaques in Alzheimer’s disease (AD) in‐vitro and in‐vivo in AD animal models.ResultWe show that RSV and HSV‐1 accumulate rich protein corona layers that are unique for each biological fluid. Moreover, we show that corona pre‐coating differentially affects viral infectivity and immune cell activation. Additionally, we demonstrate that viruses can bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface‐assisted heterogeneous nucleation. Importantly, we show that HSV‐1, which has been implicated in AD, catalyzes the nucleation and accumulation of the Aβ42 peptide both in‐vitro and in‐vivo.ConclusionOur results provide a proof‐of‐concept for the presence of an extensive and dynamic viral protein corona layer that is critical for viral‐host interactions. Unlike the viral genome‐coded surface proteins, the viral protein corona is an acquired structural layer that is dependent on the viral microenvironment resulting in different viral identities based on the target tissue and the target organism. Additionally, the demonstration of corona‐driven heterogeneous nucleation of amyloids illustrates convergence between viral and amyloid pathologies suggesting a direct physical mechanistic link that warrants further investigation. Paper: https://www.nature.com/articles/s41467‐019‐10192‐2.
Human APOE4 carriers show different metabolic signatures than APOE3 carriers throughout Alzheimer’s disease development
Authors: Yanckello Lucille M. , Hammond Tyler C. , Ham Stephanie , Lin Ai‐Ling , Nelson Peter T. 
Published: December 2020

AbstractBackgroundApolipoprotein ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). In contrast, ε3 allele of APOE (APOE3), is neutral and doesn’t alter ones risk for AD. As AD is increasingly being viewed as a metabolic disease, the goal of this study was to investigate the metabolic differences between APOE 3/3 or APOE 3/4 in post‐mortem human brain tissue at different stages of AD progression as determined by Braak staging (BS).MethodBrain samples were obtained from the Alzheimer’s Disease Center Brain Bank at the University of Kentucky Sanders Brown Center on Aging. Samples included APOE 3/3 genotype at BS 0‐3 (n = 64) and 4‐6 (n = 36) and APOE 3/4 genotypes at BS 0‐3 (n = 17) and 4‐6 (n = 41). Samples were sent to Metabolon Inc. to determine metabolic profiles using non‐targeted UPLC‐MS/MS and GC‐MS.Result218 Metabolites were detected to be different between genotypes throughout disease progression. More specifically, 179 of the 218 differ between genotypes at BS 0‐3, whereas only 41 were different at BS 4‐6. This shows that APOE genotype differences in metabolism are much more evident in early stages of disease progression. For example, increases were seen in metabolites implicated in oxidative stress such as gamma‐glutamylthreonine in early stage APOE4 carriers compared to non‐carriers. Changes in amino acid and lipid metabolism are also seen in APOE4 carriers early in disease stages, including higher levels of histamine, tryptophan, sphainganine, and sphingadienine. The release of histamine is related to responses to brain disease and altered tryptophan levels have been correlated to intensity of dementia in AD subjects. Altered sphingolipid metabolism has also been found in AD patients.ConclusionThis study helps shed light on biochemical trends based on AD stage and APOE genotype differences. We found that APOE4 carriers had earlier changes in metabolism related to oxidative stress, amino acid metabolism and lipid metabolism, which all have all been implicated in AD progression. The findings from this study may facilitate future therapeutic development for AD prevention of asymptomatic APOE4 carriers with a precision medicine approach.
Gender differences in the perception of subjective vs. objective cognitive decline: Baseline data from the SCD‐Well Trial
Authors: Meiberth Dix U. , Schild Ann‐Katrin , Sannemann Lena , Müller Theresa , Demnitz‐King Harriet , Whitfield Tim , Schlosser Marco , Krolak Salmon Pierre , Molinuevo Jose Luis , Klimecki Olga , Wirth Miranka , Chetelat Gael , Marchant Natalie L. , Jessen Frank ,   SCD‐WELL Medit‐Ageing Research Group
Published: December 2020

AbstractBackgroundSubjectively experienced cognitive decline (SCD), particularly associated with worries, in older adults is known to be a risk factor for dementia. So far, only few studies focus on gender‐specific profiles in SCD.MethodGender differences in SCD subjects who were enrolled in the SCD‐Well trial were analyzed with regard to their perception of subjective cognitive difficulties and the corresponding objective cognitive performance. SCD‐Well is a multicenter, observer‐blinded, randomized, and controlled superiority trial (Marchant et al. 2018). Two different types of 8‐week interventions are compared within the study: a mindfulness‐ and compassion‐based intervention with a validated health education program. 147 participants (95 female) were included. Data from the SCD‐Interview (SCD‐I; Miebach et al., 2019), the Cognitive Difficulties Scale (CDS; McNair & Kahn, 1983), and different cognitive scales summarized in a modified Preclinical Alzheimer’s Cognitive Composite (PACC; Donohue et al., 2014) were analyzed for gender differences.ResultStatistical analyses revealed no gender differences concerning variables of the SCD‐I and CDS. Regarding objective cognitive performance, a significant gender effect for the PACC score with men showing lower cognitive performance was detected (U = 1859.00 , p < .05). However, only women showed a negative correlation between the PACC and reported SCD as indicated on the SCD‐I (r=‐.436, p= < .001) and CDS (r = ‐.514, p < .001): more subjective cognitive difficulties and worries were associated with lower cognitive performance. To further explore this relationship, we will analyse differences between sites.ConclusionLiterature reveals gender differences in SCD for objective cognition, neuroimaging and biomarkers (Wang & Tian, 2018). The present study supports the finding of woman performing better in a cognitive assessment than men. Moreover, it adds to this literature by showing an association between self‐perceived cognitive difficulties and actual cognitive performance in women, but not men. Further research is needed to provide a deeper understanding of gender differences in SCD, which are highly relevant for approaches on early detection of cognitive decline, which might in turn impact the choice of pre‐clinical interventions.