bluuebunny/crossref_metadata_2025_split huggingface dataset:
The peculiar internal microstructure of retinal arteries as a biomarker for Alzheimer’s disease
Authors: Kotliar Konstantin , Ortner Marion , Bilirer Mahmut , Hauser Christine , Schmaderer Christoph , Grimmer Timo 
Published: December 2020

AbstractBackgroundVascular risk factors contribute to the development of Alzheimer's disease (AD). We demonstrated previously that functional retinal arterial reaction to flicker stimulation and retinal arterial vasomotion are altered in mild‐to‐moderate AD dementia. The spatial structure of the retinal artery blood column measured along the vessel axis is termed longitudinal arterial profile (LAP). It reflects configuration of internal retinal arterial wall and can be assessed with modern in‐vivo retinal imaging. Whether LAP is altered in retinal arteries of AD patients and whether it changes during vascular constriction/dilation is investigated.Method13 patients, 72.7(67.1 – 78,6) y.o. [median(1st quartile – 3rd quartile)], with mild‐to‐moderate dementia due to probable AD fulfilling the standard diagnostic criteria (ADD); and 15 anamnestic healthy control subjects 69.2(60.9 – 71.1) y.o. without subjective/objective cognitive impairment (HC) were examined with Dynamic Vessel Analyzer (IMEDOS Systems, Jena). In retinal arterial segments of 1280 µm in length vessel diameters were measured with a spatial resolution of 10µm in order to obtain LAP at different stages of arterial reaction to flicker. Differences in amplitude and frequency of spatial vessel diameter changes were analysed using Fast Fourier Transformation.ResultThe magnitude of spatial arterial diameter changes was higher in HC than in ADD during all stages of arterial response, p<0.01. At baseline it amounted to 40(32 – 54) µm in HC and to 24(20 – 29) µm in AD. Compared to the arteries of HC power spectra of LAP in AD patients showed pronounced waves with a period of ∼200 µm during baseline and vasodilation (parameter: area under the power spectra at certain frequency range), and pronounced waves with a period of ∼100 µm during vasodilation and relaxation (p <0.05).ConclusionDynamic functional alterations of retinal arteries in AD dementia are shown using a non‐invasive in‐vivo technique. Retinal arteries of AD patients change their internal microstructure which is especially emphasized during vasodilation. Further research of retinal vascular function in AD dementia should reveal the reason for the reported structural vascular alterations. Since dynamic retinal vessel analysis provides a direct non‐invasive assessment of microcirculatory damage, it could allow for additional diagnostic characterization of AD.
Disclosure of individual‐specific results to participants of a dementia prevalence study: A qualitative study
Authors: Fadda Marta , Fiordelli Maddalena , Amati Rebecca , Ibnidris Aliaa , Albanese Emiliano 
Published: December 2020

AbstractBackgroundDementia research and innovation is action area 7 of the WHO Global action plan on the public health response to dementia. Effective progress in this area depends on the promotion of participation in research both for people with and for those without dementia. However, evidence suggests that current research ethics policies and norms take participants’ preferences in little account, and may hinder equitable opportunities to take part in epidemiological research. Before conducting an epidemiological study into dementia and its impact, whose primary outcome is prevalence of dementia based on a probabilistic dementia diagnosis, we conducted a qualitative study to explore participants’ understanding of the meaning of individual‐specific results and on their preferences regarding their return.MethodBetween July 2019 and January 2020, we conducted interviews with individuals who participated in the validation phase of an epidemiological study (N = 22). Participants were 65 years old or older and resident in the Italian‐speaking part of Switzerland. We elicited information on their participation experience in the validation study, their reasons for participation (including expectations and potential barriers), their opinion on the return of research results, their understanding of these results. We also explored the communication preferences and the personal justification in favor or against the and the anticipated feelings with respect to the return of results. Finally, we discussed their preferences regarding the provision of informed consent for the return of study results. All interviews were recorded, transcribed and analyzed using thematic analysis techniques.ResultMost participants reported that researchers have a duty to share individual‐specific results with participants if requested to, and that these results must meet certain validity and reliability criteria. The main reasons in support for the return include the desire to know/ exclude oneself dementia diagnosis, and the need to establish a relationship of mutual trust between researchers and participants.ConclusionIn the context of an epidemiological study on dementia, researchers should demonstrate the validity of individual results (including dementia diagnosis) and offer in advance to participants the opportunity to receive this information accounting for their preferences and values.
Genome‐wide association analysis of neurofibrillary tangle burden identifies novel risk loci in the adult changes of thought (ACT) and the religious orders study and memory and aging project (ROSMAP) autopsy cohorts
Authors: Mukherjee Shubhabrata , Fardo David W. , Gibbons Laura E. , Larson Eric B. , Schneider Julie A. , Montine Thomas J. , Keene C. Dirk , De Jager Philip L , Bennett David A. , Crane Paul K. , Thornton Timothy A. 
Published: December 2020

AbstractBackgroundNeurofibrillary tangle (NFT) deposition is a hallmark for neuropathological diagnosis of late‐onset Alzheimer’s disease (LOAD). We were interested in identifying genetic variants associated with NFT burden in brain tissue from participants in the Adult Changes in Thought (ACT) and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.MethodIn ACT, NFT (paired helical filament (PHF)‐tau) is measured using histelide in frontal, temporal and parietal cortex. In ROSMAP, NFT burden is quantified by microscopic examination of silver‐stained slides from hippocampus and midfrontal, midtemporal, inferior parietal, and entorhinal cortex. In each cohort, we used Confirmatory Factor Analysis (CFA) to derive composites for NFT burden. We ran null models adjusting for sex and age at death; residuals were phenotypes for genetic analyses. We ran genome‐wide association studies (GWAS) of NFT burden using 1000G imputed data (NCBI; build 137) from European ancestry participants using Q‐ROADTRIPS which uses an empirical correlation matrix to account for population substructure. We performed meta‐analysis using the adaptively‐weighted Fisher’s method. Due to modest sample size and use of p‐values alone in meta‐analysis, we used conservative criteria for candidate loci, with minor allele frequency (MAF)> 0.05, meta‐analytic p‐value < 5 × 10−8, and p‐value < 0.2 in each cohort. We used generalized linear models for the top SNPs to investigate direction of effects.ResultMean death ages were 89 (ROSMAP, n = 1,225) and 87 (ACT; n = 388); and 66% (ROSMAP) and 53% (ACT) were female. A single factor CFA model fit in ACT. A bi‐factor model with a secondary factor comprising midfrontal, midtemporal, and inferior parietal cortices was needed for ROSMAP. We identified two novel loci at LRP1B (Chr 2: rs10496895; Pmeta = 1.54 × 10−8) and upstream of ZHX2 (Chr 8: rs56258958; Pmeta = 4.9 × 10−8) apart from SNPs near APOE.ConclusionLDL receptor related protein 1B (LRP1B) has restricted expression in human tissues and binds to several extracellular ligands, including fibrinogen and APOE‐ carrying lipoproteins. Zinc‐finger and homeodomain protein 2 (ZHX2) is specifically expressed in neural progenitor cells during cortical neurogenesis. Further functional enrichment analysis is needed to determine whether these novel loci may provide targets for interventions to ameliorate LOAD.
miR‐9 could mediate the relationship between childhood maltreatment and depression
Authors: He Cancan , Wang Qing , Xie Chunming 
Published: December 2020

AbstractBackgroundChildhood maltreatment (CM) is regarded as an important risk factor for major disorder depression (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear.PurposeTo explore the neural basis of the effects of CM on MDD and the potential effects of microRNA‐9 (miR‐9) in mediating these processes.MethodForty unmedicated MDD patients and 34 healthy controls (HCs) completed resting‐state fMRI scans and peripheral blood miR‐9 tests. The neural substrates of CM, miR‐9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) network were investigated in MDD patients. Two‐step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR‐9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs.ResultMDD patients showed higher miR‐9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR‐9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal‐striatum pathway and limbic system. The connection of amygdala to prefrontal‐limbic circuits separately mediated the effects of CM severity on the miR‐9 levels, and the impacts of miR‐9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR‐9 levels, CM severity, and AFC strength in prefrontal‐limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%).ConclusionMiR‐9 may play a crucial role in the process of CM experience‐produced brain changes targeting prefrontal‐limbic regions and that subsequently leads to depression. The present neuroimaging‐epigenetic results provide new insight into our understanding of MDD pathophysiology.
Multiomics approaches reveal a link between the MS4A gene loci, TREM2, and microglia function
Authors: You Shih‐Feng , He June , Filipello Fabia , Brase Logan , Del‐Aguila Jorge L. , Mihindukulasuriya Kathie A. , Benitez Bruno A. , Cruchaga Carlos , Harari Oscar , Karch Celeste M. 
Published: December 2020

AbstractBackgroundSoluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We recently identified common variants in the membrane‐spanning 4‐domains subfamily A (MS4A) gene region that were associated with CSF sTREM2 concentrations. One variant (rs1582763) was associated with increased CSF sTREM2 and reduced AD risk, while a second variant (rs6591561) was associated with reduced CSF sTREM2 and increased AD risk. Using human induced pluripotent stem cell‐derived microglia, we found that MS4A4A and TREM2 colocalize on lipid rafts at the plasma membrane. Here, we sought to define the molecular mechanism by which variants in the MS4A gene region impact sTREM2, microglia function and AD risk.MethodsTo define the functional effects of MS4A variants, we used genotype and bulk RNAseq data from 579 human brain samples. We then evaluated microglia specific effects using single nuclei RNAseq data obtained from 70 human brains.ResultsLeveraging genotypic and transcriptomic data in human brain tissue, we found that rs1582763 and rs6591561 alter distinct molecular pathways. Rs1582763, which confers AD resilience, impacts pathways associated with cholesterol metabolism, while rs6591561, which confers AD risk, impacts pathways associated with chemokine regulation. Using single nuclei RNAseq data in human brain tissue, we found that variants in the MS4A gene region were sufficient to alter specific microglia populations.ConclusionsThese findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk‐variant carriers but also in those with sporadic disease.
A multifactorial training program for cognitive, metacognitive and social participation enhancement of self‐validated older adults from Argentina: Preliminary results
Authors: Feldberg Carolina , Tartaglini María Florencia , Hermida Paula , Natalia Irrazabal , Quian Rosario , Somale Maria Veronica , Garcia Claudia , Garcia Lydia Moya 
Published: December 2020

AbstractBackgroundThe prevalence of cognitive disorders in the elderly population increases with time. Cognitive intervention is a broad field that uses different means to increase or maintain these capacities. Multifactor programs work with several aspects involved in cognitive processing simultaneously incorporating cognitive, metacognitive and psychosocial strategies. The aim of the present study is to implement and asses the efficacy of a multifactorial program for cognitive and metacognitive enhancement of self‐validated older adults.MethodDesign: Comparative, pre‐post, longitudinal intervention study. Self‐validated subjects over 60 years. Mental Fit participants (n= 47) (M= 70,04 years old; ds= 8.07 years) and controls in the community(n= 57) (M= 69.92 years old; ds= 7.31 years) were assed at the begging and at the end of the program. Instruments: Questionnaire of Social Demographic Data (built ad hoc), Brief Neuropsychological assessment for memory and attention. Metacognition: Metamemory Questionnaire, Inventory of Verbal Episodic Memory Self‐efficacy. Procedure: All the participants of the Intervention group took part in the "Memory Fit" seminar. The “Memory Fit” seminar has a duration of 8 sessions of 90 minutes each, where theoretical and practical tools are provided to improve cognitive performance in everyday life and they were also invited to take part in other activities like academical, artistic workshops, and specialist's talks about healthy habits. Controls were assed twice with eight weeks of difference between the first and second evaluation.ResultsResults reveal that when comparing the groups, statistically significant differences can be observed in favor of Mental Fit participants in: memory self‐efficacy measures before intervention (M=7.5 , SD=1.93) and after (M=8.26 , SD =1.91 t (‐2.5)= ; p <.01, metamemory before (M=119,80, SD=16.96) and after (M=135,41 , SD =19.68 t (5.06)= ; p <.000, and delay recall of a word's list before(M=7.17 ;SD=2.4)and after (M=8.05 , SD =2.5 t (‐2.6)= ; p <.01.ConclusionOur findings concur with those presented in scientific literature and support the WHO recommendations regarding the need to implement intervention programs for older adults. The inclusion of cognitive training is an approach that can help cognitively vulnerable older adults and promote healthy cognitive aging.
The expression of P2X7 receptor in human induced pluripotent stem cell‐derived cellular model of Alzheimer’s disease
Authors: Francistiova Linda , Téglási Annamária , Kern Zsófia , Kobolák Julianna , Dinnyés András 
Published: December 2020

AbstractBackgroundWe aim to elucidate the role of the purinergic receptor P2X7 in the development and progression of the Alzheimer’s disease (AD) pathology in human induced pluripotent stem cell‐derived cellular model. Our model consists of iPSC‐derived mixed neuronal and astrocytic cells, together with human iPSC‐derived microglia‐like cells. Since jointly with amyloid‐β and tau pathology, neuroinflammation presents one of the main factors in AD. Thus, having microglia in the cellular model of AD is unavoidable.MethodiPSC‐derived neuronal cultures were generated using the dual SMAD inhibition protocol, while microglial cells were generated through a 3D differentiation protocol, using bone morphogenetic protein 4 (BMP4), vascular endothelial growth factor (VEGF), and stem cell factor (SCF). Further differentiation was forced by adding macrophage colony‐stimulating factor (M‐CSF) and interleukin‐3 (IL‐3). Expression of cellular markers, as well as the studied P2X7R, was verified via ELISA, immunocytochemistry, western blot and RT‐qPCR.ResultOur neuronal cell cultures obtained from AD patients have been previously reported to show major pathologic signs of AD, thus, suitable for AD modelling. The acquired microglia‐like cells expressed Iba1, CX3CR1, CD11c, and TMEM119, which confirms their suitability for further use. Both neuronal and microglial cells express the investigated P2X7 receptor. Moreover, based on our preliminary results, the expression of P2X7R in neurons seems to be diminished when co‐cultivated with microglia. This might suggest a temporary modulatory mechanism, activated to supplement the function of the receptor in the absence of microglia.ConclusionBased on our results, the presented cellular system offers an excellent model that can be used for studying the molecular basis of age‐related neurodegenerative diseases such as Alzheimer’s disease. Future experiments will explore the effects of P2X7R antagonism on AD pathology in our cellular model. P2X7R seems to be actively engaged in AD pathological processes, and thus, the modulation of the receptor’s activity with antagonists might present a good therapeutic approach for AD. Therefore, this research helps to validate the correlation between animal and human studies of P2X7R; and will be extended to the evaluation of the therapeutic potential of selected P2X7R antagonists in Alzheimer’s disease.
Label‐free X‐ray technique for distinguishing 5XFAD from wild‐type mice
Authors: Dahal Eshan , Crentsil Jasson , Ghammraoui Bahaa , Badano Aldo 
Published: December 2020

AbstractBackgroundWe recently proposed a label‐free method based on spectral small‐angle x‐ray scattering (sSAXS) technique that estimates brain amyloid load in vivo in small animals. Here we present the first results of amyloid load mapping for an Alzheimer’s disease mouse model without using contrast agents.MethodA prototype sSAXS system was built to collect elastic x‐ray scattering data from an intact mouse head at angles less than 10° and energies between 30 and 45 keV. 5XFAD mice along with age‐matched wild‐type (WT) controls were used in the study. Fixed mice heads were scanned from eye to ear at three different heights in a sagittal plane with a scanning step size of 2 mm. Data were acquired at each position for 300, 600, and 1200 seconds with repositioning of the target. The relative amyloid load was estimated by taking area‐under‐the‐peak (AUP) in the scattering profile from momentum transfer (q) 3.6 to 8.4 nm‐1. AUP analysis covers the characteristic signal of amyloid plaques associated with its beta‐sheet structure.ResultOut of 15 scanned locations in mice heads using 300 s exposure time, areas associated with the isocortex and the olfactory bulb showed significantly increased AUP values with respect to WT mice. Midbrain regions showed negligible differences in AUPs. These results were further reproduced using 600 and 1200 s exposure times. Compared to WT, 5XFAD mice exhibited significantly elevated levels of amyloid plaques in the isocortex near hippocampus (9.3 ± 3.7%) and the olfactory bulb (10.8 ± 0.82 %). Our method was sensitive enough to differentiate brain regions with and without plaques despite the strong background scattering signal from the skull and other brain tissues.ConclusionOur results showcase the capability of sSAXS based method to differentiate non‐diseased and diseased mice by estimating amyloid load in Alzheimer’s disease mouse model ex vivo or in vivo and without using any contrast agent. Intrinsic small‐angle x‐ray scattering signal from beta‐amyloid plaques in diseased mice with advanced Alzheimer's allows the differentiation of brain regions with a high amyloid load.
A longitudinal study of gait on fall risk and disease progression in patients with mild cognitive impairment and Alzheimer's disease
Authors: Nocera Joe R , Gregory Gregory J , Lah James J , Levey Allan I 
Published: December 2020

AbstractBackgroundThe evaluation of gait has gained popularity in clinical practice due to its sensitivity for identifying functional decline and fall risk in numerous patient populations. Specific to Alzheimer’s Disease (AD), previous research has shown higher risk of falls and increased disability when compared to their healthy counterparts. However, gait biomarkers that can predict fall risk, disability and disease progression in those with AD have not been adequately quantified. A better characterization of longitudinal gait changes in patients with dementia could have implications for future research and targeted interventions aimed to identify and lessen fall risk as well as the related disability.MethodsGait outcomes, including gait speed, step length variability and step symmetry were collected at two timepoints using an instrumented ProtoKinetics Gait Mat. Each gait collection was linked to the electronic medical record in order to obtain a disease diagnosis and fall history.ResultsThe final sample included 70 patients that were classified as mild cognitive impairment (MCI) at gait timepoint 1 and remained MCI at gait timepoint 2 (MCI‐MCI), 84 patients that were classified as AD at gait timepoint 1 and remained AD (AD‐AD) and 17 that were classified as MCI at gait timepoint 1 and subsequently transitioned to AD at gait timepoint 2 (MCI‐AD). Across the groups, gait speed was significantly slower in those with a history of falls when compared to those without a fall history (p<0.05). Fall rates were highest in the AD‐AD group (41%). At gait timepoint 1, there was no significant difference in age or MOCA between the MCI‐MCI and MCI‐AD groups, however, fall rates were higher for those that transitioned from MCI to AD (24%) versus those that remained MCI from timepoint 1 to 2 (16%).ConclusionThe results demonstrate there is a high risk of falls among patients with AD and those that transition from MCI to AD. A slower gait speed was associated with higher fall risk across groups. The significant rate of falls highlights the need for targeted interventions as falls are associated with increased disability, hospitalization and mortality.