bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of microRNA‐451a in the blood of the patients with Alzheimer’s disease (AD)
Authors: Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Borawska Renata , Doroszkiewicz Julia , Kaczynska Aleksandra , Litman‐Zawadzka Ala , Slowik Agnieszka , Mroczko Barbara 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disease, that characterize a long preclinical phase. Therefore, improving the early diagnosis of the disease is crucial. Biological and cognitive markers that will help improve the accurate diagnosis of the disease, understanding the underlying etiology of the clinical syndrome and that can be useful in clinical trial recruitment are constantly sought. It has been suggested that changes in miRNAs expression may predict the onset of cognitive decline. Measuring miRNA in the blood could be a promising approach for the early detection of AD. The literature data have indicated that circulating miRNAs could reflect the early neurodegenerative changes and predict the MCI/AD onset during the pre‐symptomatic stage. This study aims to evaluate the concentration of the miRNA‐451a in patients with AD and compare it with classical biomarkers for the disease.MethodA total of 30 individuals, including 15 patients with AD and 15 non‐demented controls, were enrolled in the study. miRNA was isolated from serum samples, and it was hybridized with the biotin‐labeled specific DNA oligonucleotide. The RNA hybrids were then transferred onto a stationary solid phase coated with a monoclonal antibody specific to matched RNA‐biotin hybrids. The absorbance of the complex was proportional to the concentration of miRNA‐451a present in the serum sample. The classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau, and pTau181, were assessed in the cerebrospinal fluid (CSF) by immunoenzyme assays.ResultThe significantly higher concentrations of miRNA451a in AD patients in comparison to non‐demented controls were revelded. Moreover, the elevated level of miRNA451a correlated significantly with Aβ‐42/Aβ‐40 ratio and tau protein in the whole study group.ConclusionPresented results indicate that miRNA451a deregulation may be important in the initiation of AD‐related neurodegeneration, but these investigations need to be further clarified using a larger study group.AcknowledgementThe study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Comparison of automated CLEIA and manual ELISA immunoassays for CSF AD biomarkers: The Fundació ACE Biomarker Research Program (FACEBREP)
Authors: Orellana Adelina , Valero Sergi , Abdelnour Carla , Montrreal Laura , de Rojas Itziar , Rosende‐Roca Maitee , Mauleon Ana , Vargas Liliana , Tartari Juan Pablo , Esteban‐De Antonio Ester , García‐González Pablo , Alarcón‐Martín Emilio , Alegret Montserrat , Alcolea Daniel , Lleó Alberto , Hernandez Isabel , Tarraga Lluis , Marquié Marta , Boada Mercè 
Published: December 2021

AbstractBackgroundClinical diagnosis of Alzheimer’s disease (AD) increasingly incorporate CSF biomarkers. However due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, it is recommended to establish in‐house cutoffs defining the positivity/negativity of CSF biomarkers.MethodWe quantified CSF Aβ1‐42, t‐Tau, p181Tau and Aβ1‐40 with standard INNOTEST® ELISA and Lumipulse G® chemiluminescence enzyme‐immunoassay (CLEIA) performed on automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with Alzheimer Disease (AD, n=37) and amyloid‐negative Subjective Cognitive Decline subjects (SCD, n=45), cognitively stable during 3‐years and with no evidence of brain amyloidosis in 18F‐Florbetaben‐labeled positron emission tomography (FBB‐PET). To compare both methods, a subset of samples for Aβ1‐42 (n=519), t‐Tau (n=399), p181Tau (n=77) and Aβ1‐40 (n=44) were analyzed. Kappa agreement of single biomarkers and Aβ1‐42/Aβ1‐40 was performed in an independent group of mild cognitive impairment (MCI) and dementia patients (n=68).ResultCutoffs values of Aβ1‐42 and t‐Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1‐40 and 0.96 for p181TAU. Passing‐Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1‐40. Bland‐Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers were good but lower for Aβ1‐42/Aβ1‐40.ConclusionWe established internal cutoffs to discriminate AD patients from amyloid‐negative SCD individuals. Results obtained by both methods are not interchangeable but showed good agreement. We propose automated CLEIA as a good alternative to manual ELISA together with Aβ1‐42/Aβ1‐40 to classify amyloidosis.
Reduction of behavioural inhibition disorders in behavioural variant frontotemporal dementia patients observed under semi‐ecological conditions
Authors: Tanguy Delphine , Batrancourt Bénédicte , Bouzigues Arabella , Godefroy Valérie , Bendetowicz David , Rametti‐Lacroux Armelle , Bombois Stéphanie , Cognat Emmanuel , Le Ber Isabelle , Morandi Xavier , Jannin Pierre , Levy Richard , Migliaccio Raffaella 
Published: December 2021

AbstractBackgroundBehavioural variant frontotemporal dementia (bvFTD) is characterised by a progressive deterioration of personality, social conduct and cognition. Especially, inhibition troubles are reported, impairing the daily lives of patients and caregivers. However, assessment and characterisation of disinhibition are still poorly known, leading to a limited management of these disorders. We aim to identify activities related to an increase or a decrease of behavioural disinhibition, in order to better apprehend these disorders and set up non‐pharmacological approaches to limit these troubles.MethodWe assess behavioural disinhibition in a semi‐ecological setting, noting occurrences of 16 behaviours – derived from clinical criteria of bvFTD – related to compulsivity, impulsivity or social disinhibition, in a population of 25 bvFTD and 25 healthy controls (HC). Subjects are placed in a waiting room during 45 minutes, instructions are to get comfortable and enjoy the room. During the scenario, they are firstly free to explore the room (Free Phase) and are then guided by a questionnaire to be filled in (Guided Phase). Duration of activity related behaviours and motor patterns are also collected to look for correlations with behavioural disinhibition scores.ResultTo date, we included 22 bvFTD and 24 HC. We found out that disinhibition behaviours are not constant during the scenario. BvFTD patients are less impulsive during the guided phase compared to the free phase (p=0.014, Wilcoxon test), and show more social disinhibition than HC during the free phase and at the end of the guided phase (p=0.014 and p=0.026 respectively, Mann‐Whitney U tests), but not during the guided phase. Compulsive behaviours remain unchanged. Moreover, looking for correlations between behavioural disinhibition and activity related behaviours or motor patterns, we found out that: 1) social disinhibition would be less present during activity (eg, reading), 2) there would be less compulsivity when patients are dealing with the questionnaire, and 3) impulsivity would increase during exploration of the room (eg, books).ConclusionThis study relying on a semi‐ecological setting highlights interesting areas for non‐pharmacological treatments of behavioural disturbances in bvFTD, consistent with previous studies encouraging concentration on a given task, hobbies or a tidy environment to reduce undesired behavioural symptoms in dementia.
SUVN‐I6107: Efficacy and safety assessments of a true muscarinic M1‐positive allosteric modulator for the treatment of dementia
Authors: Abraham Renny , Subramanian Ramkumar , Grandhi Venkata Ramalingayya , Muddana NageswaraRao , Kamuju Venkatesh , Badange Rajesh Kumar , Reballi Veena , Nirogi Ramakrishna 
Published: December 2021

AbstractBackgroundM1 muscarinic agonist has failed in time past in clinical trials to treat dementia observed in the elderly on account of its side effect profile. In the current investigation, we evaluated efficacy and safety of SUVN‐I6107 an M1‐positive allosteric modulator (PAM) in various animal models and compared it with earlier M1‐PAMs.MethodIn‐vitro characterization of SUVN‐I6107 was done using the reporter gene assay and radio‐ligand binding assay at muscarinic receptors. SUVN‐I6107 was evaluated for efficacy and compared with earlier M1‐PAMs. An extensive characterization of SUVN‐I6107 was carried out to understand the margin of safety in various animal models. Earlier M1‐PAMs were also assessed as a comparator.ResultBased on the reporter gene assay and radio‐ligand binding studies, SUVN‐I6107 was characterized as a M1‐PAM with no agonist like activity. No notable effects were observed at other muscarinic receptors subtypes (M2, M3, M4 and M5). SUVN‐I6107 was found to reverse time, and scopolamine induced memory deficits in various animal models of cognition. SUVN‐I6107 did not show any spike potentiation effect in agonist mode of testing (slice electrophysiology), which indicates that it has no M1 agonist like effect. Cholinergic signs were not observed at doses which were efficacious in the cognition studies. Cholinergic signs were observed several folds higher than the efficacious doses. SUVN‐I6107 was found to be safer than the earlier M1‐PAMs sans several of the characteristic side effect profile.ConclusionDoses of SUVN‐I6107 which exhibited procognitive activity were several folds lower than the doses where cholinergic signs were seen in animals. Earlier M1‐PAMs did not have a wide margin of safety in comparison to the efficacious dose.
Optimal parametric imaging methods for dual‐time‐window [18F]flutemetamol and [18F]florbetaben PET studies
Authors: Heeman Fiona , Yaqub Maqsood , Hendriks Janine , Bader Ilona , Barkhof Frederik , Gispert Juan Domingo , Van Berckel Bart N.M. , Alves Isadora Lopes , Lammertsma Adriaan A. ,   AMYPAD Consortium
Published: December 2021

AbstractBackgroundAccurate quantitative measures of amyloid beta (Aβ) plaques are needed to identify individuals with subthreshold Aβ levels or for measuring small changes over time. To this end, dynamic or dual‐time‐window scanning protocols are required. Optimal pharmacokinetic models for quantifying Aβ burden using both [18F]flutemetamol and [18F]florbetaben dual‐time‐window scans have previously been identified at a region of interest (ROI) level. This study aimed to determine optimal parametric methods for analyses of [18F]flutemetamol and [18F]florbetaben dual‐time‐window scans.MethodForty‐six participants were scanned on a PET/MR scanner using a dual‐time‐window protocol and either [18F]flutemetamol or [18F]florbetaben. The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two‐step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90‐110 min post injection interval. All parametric images were assessed visually for possible image artefacts and regional cortical outcome measures were compared with DVR derived using regional RLogan, based on AUC values for differentiating between Aβ‐positive and Aβ‐negative scans, Bland‐Altman plots and linear regression analyses.ResultVisually, RPM and SRTM2 performed best across tracers and, in addition to SUVR, provided the highest AUC values for differentiating between Aβ‐positive and Aβ‐negative scans ([18F]flutemetamol: range AUC=0.96‐0.97, [18F]florbetaben: range AUC=0.83‐0.85). Outcome parameters of most methods were highly correlated with those of the reference method (R2≥0.87), with lowest correlations observed for MRTM2 (R2=0.71‐0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. On the other hand, bias in SUVR was high for [18F]flutemetamol (mean bias>10%), but low for [18F]florbetaben (mean bias=1%) and strongly proportional with underlying Aβ burden for both tracers.ConclusionThe best overall compromise was provided by MRTM0, followed closely by SRTM2. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression. “This work has received support from the EU‐EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (grant No 115952).”
Associations of objective and subjective sleep quality with MRI markers of brain ageing and Alzheimer’s disease
Authors: Weihs Antoine , Frenzel Stefan , Katharina Wittfeld , Obst Anne , Stubbe Beate , Berger Klaus , Fietze Ingo , Penzel Thomas , Bülow Robin , Voelzke Henry , Grabe Hans J. 
Published: December 2021

AbstractBackgroundSleep is increasingly recognised as a major risk‐factor for cognitive ageing and neurodegenerative disorders such as late‐onset Alzheimer’s Disease (LOAD). Poor sleep quality has been linked to impaired cerebral clearance of amyloid‐beta, neurofibrillary tangles and reduced cognitive function. Recent studies have also highlighted a relationship between disturbed sleep and age‐related changes in brain structure.MethodWe used ordinary least‐squared regression adjusted for age, gender, BMI, intracranial volume and APOE4‐status to investigate the associations of MRI‐based markers of brain ageing and LOAD‐related brain atrophy patterns (Frenzel et al. 2019; Janowitz et al. 2016 and Weihs et al. 2020) as well as cognitive performance in terms of the immediate and delayed wordlist recollection from the Nuremberg‐Age‐Inventory (NAI) with questionnaire and polysomnography (PSG) based measures of sleep quality in 717 subjects from the large‐scale population‐based Study of Health in Pomerania (SHIP‐Trend). We analysed the percentage of total sleep time (TST) spent in slow‐wave and rapid eye movement (REM) sleep, sleep duration, sleep efficiency and sleep latency as objective sleep quality measures and the Pittsburgh sleep quality index (PSQI) as subjective sleep quality measure.ResultWe have identified inverse associations of the percentage of TST spent in slow‐wave and REM sleep with brain atrophy related to ageing and LOAD, which was mainly driven by slow‐wave sleep, with both percentages of TST and duration showing significant inverse associations. Furthermore, there was a non‐linear u‐shaped association between sleep duration and age‐related atrophy patterns. Similar associations were found for the NAI sum score and the NAI delayed recollection sub‐score, but neither were significant after correcting for multiple testing. No associations with the PSQI score were found.ConclusionWe identified associations between PSG based sleep quality markers, but not subjective sleep quality, and brain atrophy related to ageing and LOAD. With no treatment being yet available, improving objective sleep quality, especially slow‐wave sleep, could prove a viable target to slow‐down the process of cognitive decline and reduce the risk of neurodegenerative disorders such as LOAD.
Amyloid and APOE4 status interact with age on different medial temporal lobe subregions in cognitively unimpaired elderly
Authors: de Flores Robin , Demeilliez‐Servouin Solène , Kuhn Elizabeth , Chauveau Lea , Landeau Brigitte , Delcroix Nicolas , Gonneaud Julie , Chetelat Gaël 
Published: December 2021

AbstractBackgroundMedial temporal lobe (MTL) subregions, more specifically the CA1 subfield of the hippocampus and the entorhinal cortex (ERC), are particularly affected in Alzheimer’s disease (AD). However, the specific impact of amyloid (Aβ) pathology and APOE ε4 on MTL subregional atrophy remains relatively unknown. Our aim was to uncover these effects to further our understanding of the mechanisms underlying MTL atrophy in the context of AD.MethodWe used baseline data from 132 unimpaired older adults (mean age: 68.9 ± 3.8 years) from the Age‐Well randomized controlled trial for whom high‐resolution structural MRI (T2‐weighted; 0.4x0.4x2.5mm3), amyloid‐PET (Florbetapir) and APOE genotype were available. Participants were dichotomized into amyloid positive (Aβ+, n=27) and negative (Aβ‐, n=105), and APOE ε4 carrier (ε4+, n=36) and non‐carriers (ε4‐, n=96). Hippocampal subfield (CA1, CA2, CA3, dentate gyrus, subiculum) and extra‐hippocampal region (entorhinal cortex [ERC], Brodmann area [BA] 35 and 36, and parahippocampal cortex [PHC]) volumes were estimated using ASHS and normalized by total intracranial volume. For each subregion, group comparisons were performed (Aβ+ vs Aβ‐ and ε4+ vs ε4‐) using ANCOVAs, including age, sex and education as covariates. Interactions with age (i.e., Aβ status * age and APOE ε4 status * age) were also investigated for each subregion.ResultNo significant differences were observed between Aβ+ and Aβ‐, nor between ε4+ and ε4‐. However, significant Aβ status * age interactions were observed for CA1 and PHC (p<0.05), where volumes were negatively associated with age in the Aβ+ group only (figure 1). In addition, a significant APOE ε4 status * age interaction was found for ERC (p<0.05), where volume was negatively associated with age in the ε4+ group only (figure 2).ConclusionOverall, our analyses showed that Aβ and APOE ε4 status differentially interact with age on MTL subregions (CA1/PHC and ERC, respectively) in cognitively unimpaired elderly. These observations suggest that the atrophy of MTL regions that are specifically altered in AD relies on distinct mechanisms involving amyloid pathology and APOE ε4. These results are particularly important to develop MRI‐based biomarkers to detect early AD and further our understanding of MTL atrophy in normal and pathological ageing.
Association between late‐life neighborhood built environment and cognitive impairment in older adults
Authors: Chen Ting‐An , Chen Jen‐Hau , Yu Hwa‐Lung , Chen Ta‐Fu , Yeh Su‐Ling , Chen Yen‐Ching 
Published: December 2021

AbstractBackgroundElders’ mobility and social activities are closely related to their living environments and cognitive function. Built environments and social activities tend to vary across populations and geographic regions. Therefore, this study aims to explore the association between late‐life neighborhood built environment and cognitive function in community‐dwelling older adults.MethodsThis prospective cohort study recruited 605 participants aged 65 or older from senior health checkup program at a tertiary medical center at baseline (2011‐2013) with three biennial follow‐ups. After excluding participants with suspected dementia, stroke, brain tumor, incomplete or changing residential address between 2005 and 2011, 465 participants remained for analyses. Global and domain‐specific cognition (memory, attention, executive function, and language) were assessed at baseline and each follow‐up. Built environment data was obtained from 2005 land use survey in Taiwan. Two buffer zones (500 m and 1000 m) centering at each participant’s residential address were created to assess built environment by the following indices: (1) the percentage of public open space, (2) the number of cultural resources, and (3) sports venue. Generalized linear mixed models were used to explore the association between built environment and global or domain‐specific cognitive function adjusting for age, sex, socioeconomic status, apolipoprotein E e4 status, physical activity, physical function and chronic conditions.ResultsOver six years, more public open space was associated with better logical memory delaying theme recall (within a 1000‐m buffer: β=2.17), more cultural resources were associated with poor executive function (Trail Making Test A, within a 500‐m buffer: β=‐0.078). For every 1 year increment, more public open space was associated with poor executive function (Trail Making Test B, within a 1000‐m buffer: β=‐0.52), more cultural resources was associated with better executive function (within a 1000‐m buffer: β=0.006) and poor logical memory delayed theme recall (within a 500‐m buffer: β=‐0.019). No significant association was found for sports venues in relation to cognition.ConclusionWe found that different neighborhood built environment was associated with the performance of specific cognitive domains. Findings from this study indicate that choosing proper neighborhood environment may prevent cognitive impairment in the preclinical stage of dementia.
Dynamic functional connectivity patterns associated with Alzheimer’s disease risk and protective factors
Authors: Dautricourt Sophie 
Published: December 2021

AbstractBackgroundRegions of high functional connectivity (hubs) are particularly sensitive to Alzheimer’s disease (AD). Dynamic functional connectivity (DFC) recently emerged as a powerful technique to reflect changes in functional connectivity over a short time. In this study, we used resting‐state DFC to investigate whether transient connectivity configurations are associated with AD risk and protective factors.MethodWe collected resting state fMRI data in 127 healthy older adults from the Age‐Well cohort. We estimated DFC using a sliding window approach to identify the transient connection between the default mode network (DMN), the salience network (SN) and the executive control network (CEN) and identify different states using k‐mean clustering. Stepwise regression analyses were used to assess the relationship between the time spent in each state, the number of transitions between states and AD risk factors and biomarkers, including cardiovascular factors, depression, lifestyle (Lifetime of Experiences Questionnaire (LEQ), Cognitive Activity Questionnaire (CAQ)), cognition (Preclinical Alzheimer’s Cognitive Composite 5 (PACC5)), neuroimaging biomarkers (amyloid burden, glucose metabolism and hippocampal volume) and APOE4 status.ResultWe identified four states (Figure 1). Longer time spent in a configuration characterized by strong connections between all networks (State 1), was associated with higher scores in the CAQ (β=0.27, P=0.001) and PACC5 (β=0.25, P=0.011). More time spent in State 2, where the DMN is disconnected from the other networks, was associated with higher scores in the LEQ (β=0.21, P=0.015) and absence of hypertension or cholesterol. The time spent in a configuration where all networks are weakly connected (State 3), was associated with lower scores in the CAQ (β=‐0.23, P=0.001) and LEQ (β=‐0.22, P=0.007). The time spent in State 4, where the SN is disconnected from the other networks, was associated with lower hippocampal volume (β=‐0.19, P=0.040). Finally, higher number of transitions between states was associated with higher amyloid burden (β=0.21, P=0.025).ConclusionDistinct DFC patterns are differentially associated with AD risk. We were able to identify two DFC states associated with increased AD risk and two states associated with AD protective factors. These findings shed new lights on the dynamic neural mechanisms underlying reserve and vulnerability in healthy older adults.