bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of specific gray matter volumes to insomnia severity
Authors: Martínez Neus Falgàs , Allen Isabel Elaine , Mumford Paige S , Essanaa Youssef M , Le Michelle M , You Michelle , Grinberg Lea Tenenholz , Neylan Thomas , Rosen Howard J , Kramer Joel H , Walsh Christine M 
Published: December 2020

AbstractBackgroundThere is an increasing awareness that sleep disturbances are a risk factor for dementia (Sindi, 2018). Prior case‐control studies have suggested that certain alterations in brain structure could be associated with insomnia status (Sexton, 2014; Grau‐Rivera, 2019). Specifically, they mainly described smaller cortical volumes in orbitofrontal and cingulate areas. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia. Therefore, our goal was to investigate the association between gray matter (GM) and white matter (WM) regions with insomnia severity. We hypothesized that a smaller orbitofrontal and cingulate cortex is associated with greater insomnia severity.Method122 healthy subjects (age 74.7±5.7 years old, 55.7% female) were recruited from the Healthy Aging Study at Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), a subjective measure of insomnia (Bastien, 2001). FreeSurfer was used to obtain GM and WM volumes. We used linear regression models to evaluate the relevance of regional GM and WM volumes to ISI, controlling for age and total intracranial volume.ResultDistribution of ISI scores ranged from 0 to 16 (4.8±4.2). Regression models showed that smaller pars orbitalis (β=‐0.29, p=0.008), supramarginal (β=‐0.26, p=0.019), transverse temporal (β=‐0.24, p=0.018), postcentral (β=‐0.24, p=0.027), rostral anterior cingulate (β=‐0.23, p=0.044) and isthmus cingulate (β=‐0.23, p=0.045) GM regions were associated with higher ISI scores. White matter regions were not associated with ISI.ConclusionLower volumes in certain cortical regions contributed to a higher degree of perceived insomnia severity. Conversely, white matter regions had no effect. Our results not only reinforce the involvement of orbitofrontal and cingulate regions with the presence of insomnia (Sexton, 2014; Grau‐Rivera, 2019) but furthermore, extend this showing that insomnia severity is associated with volumetric values in these areas. Further studies are needed to clarify how these insomnia‐related brain changes in healthy subjects align with an increased risk of dementia.
A head‐to‐head comparison between senolytic therapies, dasatinib plus quercetin and fisetin, indicates sex‐ and genotype‐specific differences in translationally relevant outcomes
Authors: Garbarino Valentina R , Tran Sydney , Glassman Jordan E , Kirkland James L , Musi Nicolas , Seshadri Sudha , Orr Miranda E 
Published: December 2020

AbstractBackgroundSenescent cells accumulate with advanced age and contribute to dysfunction and disability. We recently discovered that tau protein accumulation induces cellular senescence in Alzheimer’s disease and other tauopathies, a group of brain diseases characterized by the deposition of tau protein (Musi et al., 2018). Treating mice with senolytics, drugs that specifically target senescent cells for their removal, reduced pathology and improved brain structure and function in tauopathy mice. Our initial study focused on dasatinib plus quercetin (D+Q). We now report results from directly comparing D+Q to fisetin (FIS) to determine differences in efficacy, toxicity, and sex and genotype as we work to translate this therapy to clinical studies.MethodFourteen‐month old male and female wild type (WT) and tau transgenic (rTg4510) mice were treated intermittently (3 days on, 11 days off, for 6 cycles) with D+Q, FIS, or vehicle by oral gavage. Physical and behavioral outcomes were measured before and after treatment.ResultBoth senolytic therapies significantly enhanced female rTg4510 mouse performance in the y‐maze (increased preference for novel arm (p = 0.00093 and p = 0.0015, D+Q and FIS, respectively); no treatment changes were noted in WT females or male mice. Pre‐ and post‐treatment comparisons of body weight revealed that D+Q uniquely increased body weight in female mice (WT: p=0.0005 and t: p = 0.024). Similarly, body length was increased by D+Q in WT (p= 0.0012) and rTg4510 (p= 0.0457) females, and WT males (p= 0.0481). Physical performance measures included run speed whereby D+Q increased WT female (p= 0.0002) and male (p=0.0267) velocity. FIS only affected WT males (p= 0.0022) but not females; and rTg4510 male (p=0.0015) but not female mice. Additional genotype, sex and treatment specific effects were observed in measures of frailty, grip strength, stride length, and nerve conduction. Our on‐going analyses of brain volumetry changes (MRI), axon integrity, transcriptomics, tau pathology, and inflammatory changes among the groups will provide mechanistic insights responsible for these behavioral phenotypes.ConclusionOur study suggests that tailoring senolytic therapies to specific individuals based on sex and disease state may provide the most benefit as we translate this promising therapy to clinical use.
Functional impact of cholinergic dysfunction on retrosplenial circuits in the 5xFAD mouse model of Alzheimer’s disease
Authors: Jedrasiak‐Cape Izabela , Ahmed Omar J 
Published: December 2020

AbstractBackgroundThe retrosplenial cortex (RSC) is critical for learning, memory and spatial navigation and is one of the first brain regions to show dysfunctional activity in the earliest stages of Alzheimer’s disease. RSC receives dense cholinergic inputs from multiple basal forebrain regions. While decreased cholinergic tone is one of the hallmarks of the Alzheimer’s disease, it is not known how this change impacts retrosplenial cells and circuits. In wild‐type mice, cholinergic agonists induce persistent firing in limbic areas such as the entorhinal cortex and the prefrontal cortex. This persistent firing has been proposed as an important neuronal substrate for working memory and successful spatial navigation.MethodHere, we investigated cholinergic‐induced persistent firing in the retrosplenial cortex in the 5xFAD model of Alzheimer’s disease. We combined pharmacological and whole‐cell patch clamp techniques to characterize the response of retrosplenial cortex cells to carbachol (20 uM), a non‐specific cholinergic agonist, in both wild type and 5xFAD mice aged P30‐P75.ResultIn wild type animals, persistent firing in response to carbachol in deep layers of the retrosplenial cortex was commonly observed (66.6% of all cells tested). This persistent firing was blocked by atropine (10uM) indicating that it is dependent on muscarinic cholinergic receptors. Retrosplenial cells in 5xFAD animals rarely showed persistent firing (20%, p<0.05, binomial test comparing wild type vs 5xFAD).ConclusionCholinergic hypofunction resulting from damage to basal forebrain neurons early in Alzheimer’s disease has widely been linked to cognitive impairment. Our results point to a complementary mechanism impacting cholinergic control of cortical circuits: muscarinic receptor downregulation in the earliest stages of Alzheimer’s disease. These changes prevent retrosplenial cortex cells of 5xFAD mice from responding to cholinergic activation with the kind of persistent firing that is important for working memory and spatial navigation, suggesting a mechanistic explanation for how cholinergic dysfunction leads to impaired spatial encoding by retrosplenial circuits.
Explainable deep learning models for dementia identification via magnetic resonance imaging
Authors: Gallay Charles , Draganski Bogdan , Kherif Ferath 
Published: December 2020

AbstractBackgroundToday, to diagnose dementia, clinicians evaluate cognitive tests performed by patients and briefly analyze brain imaging data to look for biomarkers. While valuable information is present in MRI scans, these latter remain challenging to analyze and interpret. Artificial intelligence models have shown promising results to improve the current practice by supporting practitioners in the evaluation of imaging data. Nonetheless, the majority of developed statistical models are more often than not black‐box systems that issue predictions without any clear interpretability, hindering their practical applications.MethodsWe propose an interpretable method based on deep learning that works on minimally preprocessed T1‐weighted 3D scans of the brain. Relying on FullGrad [1], we can dissect the predictions of the model given an input scan. Once the model is trained, it can not only give an automated diagnostic but also generate a heatmap highlighting the regions of the brain that our model points to be responsible for its prediction of dementia. To ensure practicality, we integrate our model in a convenient app that can smoothly be run from a browser, as shown in the attached screenshot.ResultsWe trained and evaluated our model on the OASIS dataset [2]. The specific explanation obtained by our model points at well‐known biomarkers, notably by highlighting the voxels of the hippocampus of patients with dementia. Interestingly, as it can be seen in the second annex, we notice that across individuals, our model focuses more on the voxels located in the right hippocampus.ConclusionsIn this study, we show how machine learning can identify dementia patients using MRI images while ensuring interpretable decisions of the models. Our tools, including the bespoke "explainer" viewer overlaid on each patient's brain, will enable the development of better and more reliable machine‐learning based diagnostics and nurture the trust of practitioners in computer‐aided diagnostics. Furthermore, this will help to discover currently unknown biomarkers and thus lead to a better understanding of the disease. References: 1) Full‐Gradient Representation for Neural Network Visualization, Suraj Srinivas, Francois Fleuret, 2) OASIS‐3: Longitudinal Neuroimaging, Clinical, and Cognitive Dataset for Normal Aging and Alzheimer Disease, Pamela J LaMontagne.
What factors explain racial differences in memory‐related gray matter volume regions of interest among cognitively normal older adults?
Authors: Godina Sara L , Rosano Caterina , Gianaros Peter , Aizenstein Howard J , Carlson Michelle C , Rosso Andrea L 
Published: December 2020

AbstractBackgroundPrevious studies indicate there are racial differences in the prevalence of Alzheimer’s Disease or other dementias, suggesting older Blacks are about twice as likely to have dementia as older Whites. Incorporating neuroimaging measures is necessary to understand the neural pathology underlying the mechanisms of these racial disparities, however limited data exists on neuroimaging outcomes among racially diverse adults of advanced age.MethodWe examined cross‐sectional associations of race and memory‐related gray matter volume (GMV) regions of interest (ROIs) in 263 community‐sampled adults (mean age 83, 57% female, 39% Black) from the Healthy Brain Project, a substudy of the Health, Aging, and Body Composition Study. Generalized linear models were used to test associations between race and memory‐related GMV ROIs (hippocampus, posterior cingulate cortex, parahippocampal gyrus, and entorhinal cortex), quantified using magnetic resonance imaging.ResultCompared to Whites, Blacks consistently showed smaller GMV in four memory related ROIs, cross‐sectionally. Racial differences in GMV remained in the parahippocampal gyrus (β=‐433.42, 95% CI: ‐642.96, ‐233.87) and entorhinal cortex (β=‐159.18, 95%CI: ‐245.89, ‐72.48), after adjusting for demographic, environmental, and psychosocial covariates.ConclusionThe association between gray matter volume of memory‐related ROIs and race is only partially explained by the demographic, environmental, and psychosocial factors considered in the present study. Quantitative bias analysis will be used to address whether these findings are the result of selection bias due to racial differences in recruitment.
Lipid profiling of healthy and Alzheimer’s‐affected mouse brains by using DESI imaging mass spectrometry: How lipid dyshomeostasis can contribute to Alzheimer’s disease
Authors: Lazarian Artur , Menon Vilas , Fowler Brandon , McIntire Laura Beth 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is one of the biggest health challenges that we face worldwide, which causes millions of deaths annually and costs reach many billions. Yet, the cause of the disease is not fully understood and therefore no effective treatment is available up to date. Lipidomic data from autopsy brain, human plasma and animal models highlights severe lipid dyshomeostasis in AD. Thus, the disruption of lipid metabolism and the homeostasis are thought to play a crucial role in the development of Alzheimer’s pathology. The importance of lipid metabolism in AD is supported by GWAS studies which have identified multiple lipid modifying enzymes and interacting proteins. It is likely then that specific pathways in lipid metabolism underlie AD disease mechanisms leading to behavioral impairment. Specifically, previous studies have shown that the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models.MethodTherefore, it’s of high importance to screen the lipid species in both healthy and AD affected human and mouse brains. By applying Mass Spectrometry (Synapt G2‐Si), we aim at setting up a workflow for high‐throughput quantitative and qualitative lipidomics profiling for healthy and AD affected brains.ResultHere, we show the phylogenetic comparisons of genes and their SNPs that were found by GWAS studies to be risk factors in AD. These SNPs in humans were compared to that of primates and other animals. In addition, preliminary Mass Spectrometry runs were carried out for setting up a lipid screening workflow.ConclusionAs supported by our preliminary data, the MS will allow us to detect broad range of versatile lipid species by applying targeted and untargeted analysis, Ion Mobility Separation, and DESI Imaging.
Granulovacuolar degenerating body markers accumulate alongside dysfunctional lysosomes in dystrophic neurites and correlate with cognition in Alzheimer’s disease
Authors: Schrag Matthew S , Mahoney Emily R , Shostak Alena , Nackenoff Alex , Dumitrescu Logan , Akers Carolyn , Jefferson Angela L , Hohman Timothy J 
Published: December 2020

AbstractBackgroundRecent decades have brought a renaissance in understanding lysosomes and autophagy in neurobiology and neurodegenerative diseases. Neuronal endolysosomes are defective in Alzheimer’s disease (AD), most notably in dystrophic neurites where large numbers of enzymatically inactive lysosomes accumulate, distending axons around β‐amyloid plaques. Granulovacuolar degeneration bodies (GVDBs) are another well‐documented neuropathology associated with AD. These pathological neuronal organelles have two membranes, the outer containing lysosome‐associated membrane proteins suggesting these organelles are a product of frustrated autophagy. To implicate GVDBs in the pathogenesis of AD, we evaluated if GVDBs are present in dystrophic neurites and whether the expression of key GVDB genes are correlated with cognition in AD.MethodsHuman brain with AD and brains from 5xFAD mice were examined with immunohistochemistry and confocal microscopy for the established GVDB marker CK1δ. We also evaluated the recently discovered GVDB marker Golgin a4 and its binding partner ARL1 (implicated in the formation of autophagosomes). Finally, we assessed the association of mRNA levels of these genes in frontal cortex at autopsy with cognition and β‐amyloid pathology in 600 participants in Rush University’s Religious Orders Study and Memory and Aging Project (ROS/MAP).ResultsWe discovered that CK1δ, Golgin 4a and ARL1 accumulate in dystrophic neurites in mouse and human AD brain, partially co‐localizing with the lysosomal enzyme cathepsin B, indicating a portion of the organelles accumulating in dystrophic neurites are likely GVDBs. In ROS/MAP participants, golgin a4 expression inversely correlated with cognitive trajectory (β=‐0.003, p=6.0x10‐4) and β‐amyloid plaque density (β=0.01, p=0.001), while ARL1 directly correlated with longitudinal cognition (β=0.004, p=7.0x10‐4) and β‐amyloid plaque density (β=‐0.01, p=0.027) in a model covarying for age at death, sex, education, APOE genotype, and interval between last visit and death. From these results we constructed a conceptual model of the molecular interaction between dysfunctional lysosomes and dysfunctional autophagic organelles in dystrophic neurites.ConclusionsGVDBs accumulate in dystrophic neurites in AD, indicating the presence of defective autophagic organelles in addition to the known dysfunctional lysosomes. Transcriptomic data demonstrating a correlation of GVDB markers with cognition and β‐amyloid pathology suggests this discovery is likely functionally relevant.
Cognitive profile of mild behavioral impairment (MBI) in brain health registry participants
Authors: Kassam Farzeen , Chen Hung‐Yu , Nosheny Rachel L. , Williams Tirzah , Mackin R. Scott , Weiner Michael W. , Ismail Zahinoor 
Published: December 2020

AbstractBackgroundNon‐cognitive markers may be utilized in dementia risk assessments. Mild behavioural impairment (MBI) is a validated neurobehavioural syndrome developed by an Alzheimer’s Association‐ISTAART working group including the following criteria: 1) later life emergent and persistent neuropsychiatric symptoms; 2) representing a change from longstanding personality or patterns of behaviour; 3) not better accounted for by psychiatric conditions or life stressors. MBI as an at‐risk state for cognitive decline and dementia and may be the earliest manifestations of disease for some. We investigated whether MBI, measured with the MBI checklist, was associated with cognitive changes in older adults in the Brain Health Registry (BHR).MethodsWe analyzed data from 5225 participants in BHR. Participants were included if they completed Lumosity cognitive tests (memory span, reverse memory span, trailmaking, go‐no‐go) and an informant‐rated MBI‐C. We excluded participants with major neurological, psychiatric or developmental disorders. Using cutpoints to dichotomize MBI+ and MBI‐ participants (MBI‐C > 5, 6, 7), univariate ANOVA was used to determine whether people with MBI also showed impairment in cognitive test performance. ANOVAs covaried for age, sex, education, and time between test administration and MBI‐C completion. All assessments were completed remotely, using the BHR online registry.ResultsThe final sample included 802 participants with a mean age of 66.97(SD 10.71), of which 515/802 were females (64.21%). The number and percent of MBI‐C+ participants was 62 (7.7%), 53 (6.6%), and 48 (6.0%) at cutpoints of MBI‐C >5, >6, and >7 respectively. MBI+ participants had significantly poorer memory span, poorer reverse memory span, longer trail‐making completion time, and more trail‐making errors (see Table 1 for statistical reporting). A significantly greater number of men were classified as MBI+ at all 3 cutpoints (p< 0.001).ConclusionsIn a large cohort of older adults in BHR, MBI assessed remotely and unsupervised using an online interface, was associated with poorer cognition in the domains of memory and executive function compared to those without MBI. Utilizing the MBI‐C in case finding may be a simple, efficient, and scalable way to detect individuals with subtle cognitive changes, for further assessment and workup, or potential inclusion in clinical trials.
Ameisensäure‐unterstützte selektive Hydrogenolyse von 5‐Hydroxymethylfurfural zu 2,5‐Dimethylfuran über bifunktionale Pd‐Nanopartikel auf N‐dotiertem mesoporösem Kohlenstoff als Träger
Authors: Hu Bin , Warczinski Lisa , Li Xiaoyu , Lu Mohong , Bitzer Johannes , Heidelmann Markus , Eckhard Till , Fu Qi , Schulwitz Jonas , Merko Mariia , Li Mingshi , Kleist Wolfgang , Hättig Christof , Muhler Martin , Peng Baoxiang 
Published: December 2020

AbstractAus Biomasse gewonnenes 5‐Hydroxymethylfurfural (HMF) gilt als vielversprechende Plattformchemikalien zur Herstellung von 2,5‐Dimethylfuran (DMF) als flüssigen Transportkraftstoff. Pd‐Nanopartikel auf N‐haltigen und N‐freien mesoporösen Kohlenstoffmaterialien wurden hergestellt, charakterisiert und bei der Hydrogenolyse von HMF zu DMF unter milden Reaktionsbedingungen eingesetzt. Die quantitative Umwandlung von HMF zu DMF wurde in Gegenwart von Ameisensäure (FA) und H2 über Pd/NMC innerhalb von 2 h erreicht. Der Reaktionsmechanismus wurde durch Variation der Wasserstoffquelle, des Additivs und des Substrats sowie durch In‐situ‐ATR‐IR‐Spektroskopie erforscht. Die Hauptrolle von FA besteht darin, den dominanten Reaktionsweg von der Hydrierung der Aldehydgruppe zur Hydrogenolyse der Hydroxymethylgruppe über die Protonierung durch FA an der C‐OH‐Gruppe zu verlagern, wodurch die Aktivierungsbarriere der C‐O‐Bindungsspaltung gesenkt und somit die Reaktionsgeschwindigkeit deutlich erhöht wird. XPS‐Ergebnisse und DFT‐Berechnungen zeigten, dass Pd2+‐Spezies, die mit pyridinartigen N‐Atomen interagieren, die selektive Hydrogenolyse der C‐OH‐Bindung in Anwesenheit von FA aufgrund ihrer hohen Fähigkeit zur Aktivierung von FA und zur Stabilisierung von H− deutlich verbessern.
The Discrete Breast Cancer Stem Cell Mammosphere Activity of Group 10‐Bis(azadiphosphine) Metal Complexes
Authors: Xiao Zhiyin , Johnson Alice , Singh Kuldip , Suntharalingam Kogularamanan 
Published: December 2020

AbstractWe report the anti‐breast cancer stem cell (CSC) properties of a series of Group 10‐bis(azadiphosphine) complexes 1–3 under exclusively three‐dimensional cell culture conditions. The breast CSC mammosphere potency of 1–3 is dependent on the Group 10 metal present, increasing in the following order: 1 (nickel complex) <2 (palladium complex) <3 (platinum complex). Notably, 3 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC‐active compound, or any reported anti‐CSC metal complex tested under similar conditions. Mechanistic studies suggest that the most effective complexes 2 and 3 readily penetrate CSC mammospheres, enter CSC nuclei, induce genomic DNA damage, and trigger caspase‐dependent apoptosis. To the best of our knowledge, this is the first study to systematically probe the anti‐CSC activity of a series of structurally related Group 10 complexes and to be conducted entirely using three‐dimensional CSC culture conditions.
Diastereodivergent Synthesis of β‐Amino Alcohols by Dual‐Metal‐Catalyzed Coupling of Alkoxyallenes with Aldimine Esters
Authors: Zhu Minghui , Zhang Qinglong , Zi Weiwei 
Published: December 2020

AbstractBoth syn‐ and anti‐β‐amino alcohols are common structural motifs in natural products, drug molecules, chiral ligands and catalysts. However, the currently available methods for synthesizing these motifs are limited to generate only one diastereoisomer. Therefore, development of a unified method for stereoselective access to complementary diastereomers would be highly desirable. Herein, we report a method for dual‐metal‐catalyzed diastereodivergent coupling of alkoxyallenes with aldimine esters. By carefully selecting the two metals and appropriate chiral ligands, we could synthesize both syn‐ and anti‐β‐amino alcohol motifs with high enantioselectivity and diastereoselectivity from the same set of starting materials. Furthermore, stereodivergent syntheses of all four stereoisomers of β‐amino alcohols could be achieved. We demonstrated the synthetic utility of this method by concisely synthesizing two β‐amino alcohol natural products, mycestericins F and G.