bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and biomarker correlates of region‐specific diffusion MRI metrics in a short‐term, Phase 1b clinical trial for XPro1595 in Alzheimer’s disease
Authors: Pope Parris , Ridgway Gerard R , Torso Mario , Chance Steven A , Roy Maggie , Houde Jean‐Christophe , Descoteaux Maxime , Barnum CJ , Tesi RJ 
Published: December 2023

AbstractBackgroundXPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a 12‐week, phase‐1b open‐label dose finding study in patients with AD (NCT03943264). An unbiased screen of imaging outcomes revealed signals for target engagement in gray matter (GM) cortices documented in the literature as regions most frequently affected by accumulation of amyloid‐beta (Aβ) in early and late phases of AD (Mattsson et al. 2019). Post‐hoc analyses were conducted to further investigate these signals.MethodStudy results for patients (n = 9; MMSE range: 8‐27) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met inclusion criteria. Correlation matrices (uncorrected Pearson’s r) were created to compare key secondary and exploratory imaging outcomes to clinical characteristics and CSF biomarkers of AD specific pathology (Roche Elecsys NeuroToolKit). Imaging outcomes included white matter free‐water (WM‐FW) as a prespecified proxy for neuroinflammation, and GM PerpPD+. PerpPD+ represents the diffusion components perpendicular to cortical GM minicolumns and serves as an indicator of worsening GM microarchitecture when increased in AD. Due to the small sample size, the threshold for identification of informative values was set at P<0.05.ResultAt baseline, PerpPD in GM regions associated with early Aβ accumulation (insula, precuneus, isthmus and posterior cingulate, and lateral‐orbitofrontal cortices), and WM‐FW in the cingulum bundle, showed strong associations with CSF biomarkers of neurodegeneration (pTau and tTau), inflammatory gliosis (YKL‐40, GFAP and sTREM2), cognitive status (MMSE scores) and disease duration (Table1). Week‐12 results showed decreased PerpPD+ and WM‐FW in these regions, with a dose‐dependent signal concentrated in the isthmus cingulate GM and cingulum WM. Isthmus cingulate PerpPD+ ∆ (%) correlated positively with baseline Aβ42/40 and MMSE (Figure1), and negatively with duration of disease and cingulum WM‐FW, whereas cingulum WM‐FW ∆ (%) corelated with baseline pTau and tTau (Table 2).ConclusionPerpPD+ in isthmus cingulate GM and WM‐FW in cingulum WM represent potential indicators of disease activity sensitive to early treatment effects in small, proof of concept clinical trials for AD. Additional research is warranted to further elucidate these signals.
Deep Brain Stimulation for Alzheimer’s Disease and the Human Memory Circuit
Authors: Howard Calvin W , Horn Andreas , Lyketsos Constantine G. , Lozano Andres M , Fox Michael D ,   ADvance Study Research Group
Published: December 2023

AbstractBackgroundBrain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS‐induced effects.MethodsWe studied 53 amnesia‐causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1‐year post‐DBS activation scores.ResultsConnectivity between AD patients' DBS sites and a subiculum region derived from amnesia‐causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham‐first (Spearman’s rho = 0.33, p = 0.027) and stimulation‐first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole‐brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p<0.00001). Both maps showed data‐driven peaks in an overlapping subiculum region. However, DBS data showed a significant interaction effect between patient age and subiculum connectivity upon outcome in a general linear model (p = 0.031). Randomization status was controlled as a covariate and was not significant. Specifically, higher subiculum connectivity in older patients led to improved cognition, while higher connectivity in younger patients resulted in worsening cognition. The data‐driven inflection point for this interaction effect was at age 65 at any subiculum connectivity value.ConclusionOur findings suggest that lesions causing amnesia and DBS sites modulating cognition converge on common neuroanatomy. However, patient age appears to be critical variable in determining whether DBS sites connected to the subiculum result in cognitive improvement or decline. Our results provide insight into the paradox of mixed outcomes across DBS cohorts and support restricting ADvance II enrollment of fornix‐targeted DBS to patients over 65. The underlying mechanisms remain unclear, and this study must be replicated in additional datasets.
Neuropsychological Characteristics of Posterior Cortical Atrophy: A Case Series Study in Participants of the RedLat Study
Authors: Garcia Deissy Milena , Buitrago Carlos Felipe , Forero Laura Valentina , Moreno Maria Jose , Rivera Carlos , Reyes Pablo A , Matallana Diana 
Published: December 2023

AbstractBackgroundPosterior cortical atrophy is a neurodegenerative condition characterized by the deterioration of visuospatial skills, associated with the deterioration in the occipital and parietal regions of the brain, and frequently associated with the neuropathology of Alzheimer’s disease.MethodThe objective of this study is to describe the neuropsychological characteristics in a sample of five RedLat study participants diagnosed with this condition. The subjects were evaluated in cognitive areas of language, attention, memory, executive functions, and visuospatial skills with a series of neuropsychological tests.ResultThe obtained data is analyzed in a descriptive manner. The results support that alterations with visual and spatial predominance. However executive dysfunction and language alterations are present aswell.ConclusionThese findings support the understanding of posterior cortical atrophy as a heterogeneous clinical syndrome.References:Yong, K. X., Graff‐Radford, J., Ahmed, S., Chapleau, M., Ossenkoppele, R., Putcha, D., … & Harding, E. (2023). Diagnosis and management of posterior cortical atrophy. Current Treatment Options in Neurology, 1‐21.Schott, J. M., & Crutch, S. J. (2019). Posterior Cortical Atrophy. Continuum (Minneapolis, Minn.), 25(1), 52‐75. https://doi.org/10.1212/CON.0000000000000696
Carvajal Castrillón, J., Aguirre, D. C., & Lopera, F. (2010). Perfil clínico y cognitivo de la atrofia cortical posterior y sus diferencias con la enfermedad de Alzheimer esporádica tardía y familiar precoz. Acta Neurológica Colombiana, 26(2), 75‐86.Iacono, L. L., Sarotto, L., & Braccia, M. L. (2022). Atrofia cortical posterior: la “variante visual” de la enfermedad de Alzheimer. Oftalmología Clínica y Experimental, 15(2).
Time saved in disease progression for treatments in AD (including 3 monoclonal antibodies and 2 other promising treatments)
Authors: Hendrix Suzanne B. , Mallinckrodt Craig , Wassom Mitchell , Haaland Benjamin A , O'Keefe Patrick P , Dickson Samuel P. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease progression causes worsening on multiple symptoms of disease which can be measured by cognitive, functional and global scales. These scales can be thought of as surrogate outcomes for the true disease progression. The degenerative and therefore progressive nature of the disease indicates that time is a measurable gold standard against which we can assess all other outcomes. Composite endpoints and global statistical tests have been used to approximate this progression outcome since it is not directly measurable. Using time as the gold standard, one can calculate the alignment of any measure against the gold standard using a signal to noise ratio. A combination of the ADAS‐cog, ADCS‐ADL and CDR‐sb aligns more than 90% with the unmeasurable progression outcome.MethodConverting each of the clinical scales to a time scale allows us to measure progression in “disease progression” time: i.e. months of progression per month of treatment, which should be linear in nature despite any non‐linearity in the clinical scale. A recent meta‐analysis was performed and data from relevant studies have been estimated using an overall progression time metric.ResultResults for five studies of interest (three monoclonal antibodies and two other treatments) Aducanumab, Donanemab, Lecanemab, AD04, and Souvenaid show time savings range from 2 months per year to 7 months per year. Results for these five studies are presented in Table 1.ConclusionMeasuring time savings in a degenerative disease reflects the true goal of disease modifying treatments which is to slow down a progressive disease which will result in slowing of progression on all aspects or symptoms of disease. Progressive diseases would cease to be diseases at all if there was no progression of symptoms. Focusing on the clinical meaningfulness of each separate point on each outcome distracts us from this overall goal. Progression time savings is meaningful to patients, caregivers and all stakeholders and can be calculated from meaningful, clinically acceptable outcomes.
Cell cycle dysregulation in iPSC‐derived neurons from C9ORF72 carriers
Authors: Gonzalez Rodrigo Lopez 
Published: December 2023

AbstractBackgroundThe GGGGCC (G4C2) repeat expansion in the C9ORF72 is the most common genetic form of amyotrophic lateral sclerosis (ALS). We and others have uncovered the role of DNA damage, upregulation of the NHEJ repair pathway and P53 activation in the pathogenesis of C9ORF72‐related ALS. Evidence from other neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease, suggests cell cycle re‐entry of post‐mitotic neurons may be detrimental and contribute to neurodegeneration.MethodIn this study, we used several well characterized induced pluripotent stem cells (iPSC) from C9ORF72 carriers and controls and differentiate into neurons. iPSC‐derived neurons were cultured for up to two months and analyzed at different time points by gene expression and western blot analysis.ResultWe have found an age‐dependent increase in the levels of cell division markers including Ki67 and Geminin (GMNN) as well as Cyclin A2, Cyclin B1, Cyclin B2, CDK1, CDK2 and CDK4 in 2‐month‐old neurons from C9ORF72 carriers as compared to controls. When we analyzed 1‐month‐old neurons as we did not find differences between controls and C9ORD72 neurons. Moreover, we found a decrease in the levels of p21 is a cyclin‐dependent kinase inhibitor that belongs to the CIP/Kip family of CDKs inhibitors and has the ability to arrest cell cycle progression at G1/S and G2/M stages, this data indicate dysregulation of cell cycle in C9ORF72 neurons.ConclusionOur data indicates that post‐mitotic neurons from C9ORF72 repeat expansion carriers are aberrantly activating the expression of proteins related to cycle progression.
Biomarker changes and their relationships to clinical efficacy outcomes in Alzheimer’s disease
Authors: Dawson Katherine 
Published: December 2023

AbstractBackgroundBiological and clinical evidence points to Alzheimer’s disease (AD) as an amyloid‐beta (Aβ)–driven tauopathy, with Aβ and tau remaining high‐priority targets for therapeutic development. Alterations of fluid and imaging biomarkers are key indicators of underlying Aβ and tau pathological changes in the brain during AD and are important for evaluating investigational agents and assessing clinical effects efficiently (e.g., via shorter trials with fewer participants).MethodAnti‐Aβ monoclonal antibodies (mAb) and anti‐extracellular tau antibodies, as well as antisense oligonucleotides (ASO) that target intracellular tau, have been evaluated across multiple clinical studies. Outcome measures were broadly consistent across trials and assessed both clinical efficacy and longitudinal effects on fluid and imaging biomarkers of disease (e.g., those detected via cerebrospinal fluid [CSF], plasma, and imaging (positron emission tomography [PET]).ResultThe results presented here show that anti‐Aβ mAb treatment reduced amyloid and tau PET standardized uptake value ratios across multiple brain regions and also impacted CSF Aβ1‐42, CSF phosphorylated tau (p‐tau), total tau (t‐tau), and plasma p‐tau181 biomarkers of disease in a dose‐dependent manner. Relevant biomarker changes generally correlated with positive clinical effects across multiple clinical efficacy scales. Anti‐tau antibody treatment demonstrated robust extracellular tau engagement in CSF but did not show clinical efficacy or any corresponding effect on tau pathology as assessed by PET. A Phase 1b trial evaluating an ASO targeting intracellular tau demonstrated a reduction in CSF t‐tau in a dose‐dependent manner; at the end of a long‐term extension study, this ASO also reduced tau burden as assessed by PET in all brain regions examined.ConclusionResults across therapeutic targets and modalities suggest that, with disease modification, relevant changes that occur in proximal and distal fluid and imaging biomarkers are linked to clinical effects. Lessons from the anti‐tau mAb study indicate that these relationships are still maintained even where, without a clinical effect, changes in AD biomarkers are not observed. Ongoing clinical trials will continue to expand our understanding of biomarker changes in AD, the contribution of amyloid and tau to disease pathology, and the temporal dynamics of biomarker changes, and their relationships to clinical efficacy outcomes.
Inhibition of BACE1 in glial cells for enhancing clearance of amyloid plaques
Authors: Yan Riqiang 
Published: December 2023

AbstractBackgroundNeuronal BACE1 has been shown to regulate synaptic functions, and deletion of Bace1 in the brain leads to impaired synaptic plasticity. To avoid dramatic inhibition of BACE1, we aimed to understand the role of BACE1 in glial cells and to determine the function of BACE1 in either microglia or astrocytes.MethodBy utilizing the generated Bace1flox mouse model, we specifically deleted Bace1 in either microglia or astrocytes and crossed with Alzheimer’s 5xFAD mice to evaluate the changes in amyloid plaques. We also purified microglia and astrocytes from multiple mouse models to examine the transcriptomic profiles in microglia or astrocytes to determine whether BACE1 regulates cellular functions of microglia or astrocytes.ResultWe showed that targeted deletion of Bace1 in microglia significantly reduced amyloid plaque loads by enhancing clearance. Unbiased RNAseq results revealed that BACE1 facilitates transition of homeostatic microglia to stage 1 disease associated microglia (DAM‐1) while reduces DAM‐2. Mice with Bace1 deletion only in microglia exhibited no defects in synaptic functions as examined by long term potentiation assays. Mice with Bace1 deletion in astrocytes also exhibited reduction in amyloid plaque load in the early stage. Unbiased RNAseq results revealed elevation of clusterin and ApoE, two proteins known for enhancing clearance of amyloid plaques.ConclusionOur molecular and mouse genetic studies show that deletion of Bace1 in glial cells appears to have minimal effect on synaptic functions. inhibition of glial BACE1 is a potential alternative strategy for enhancing Aβ clearance for AD treatment.
Highly Ordered Hierarchical Macro–Mesoporous Carbon‐Supported Cobalt Electrocatalyst for Efficient Oxygen Evolution Reaction
Authors: Luo Lanke , Xu Jingshen , Wan Qiuhong , Han Yiting , Li Mingxuan , Cui Dingwei , Chen Runxuan , Tang Zhangrong , Cui Xinjun , Xin Xin , Li Xinchang , Xiang Yulu , Dong Haohai , Lin Liu , Sun Zemin , Sun Genban 
Published: December 2023

AbstractMetal‐organic frameworks (MOFs) and their derivatives have been extensively employed in Oxygen Evolution Reaction (OER) catalysts due to their significantly larger specific surface areas, distinct metal centers, and well‐organized porous structures. However, the microporous structure of MOFs and their derivatives presents mass transfer resistance, limiting their further development. Drawing inspiration from hierarchical structures allowing for the transport and exchange of substances in the biological world, we designed and fabricated biomimetic layered porous structures within ZIF‐67 and its derivatives. Based on this, we achieved a three‐dimensional ordered layered porous nitrogen‐doped carbon‐coated magnetic cobalt catalyst (3DOLP Co@NDC) with a biomimetic pore structure. It is found that the 3DOLP Co@NDC (352 mV @10 mA cm−1) was better than Co@NDC (391 mV @10 mA cm−1). The introduction of a three‐dimensional ordered layered porous structure is conducive to increasing the specific surface area of the material, increasing the electrochemical active area, and improving the catalytic performance of the material. The introduction of a three‐dimensional ordered layered porous structure would help to build a bionic grade pore structure. The existence of biomimetic grade pore structure can effectively reduce the mass transfer resistance, improve the material exchange efficiency, and accelerate the reaction kinetics.
Water‐based Supercapacitors with Amino Acid Electrolytes: A Green Perspective for Capacitance Enhancement
Authors: D'Alessandro Alessio , Bellani Sebastiano , Gamberini Agnese , Mastronardi Valentina , Zappia Marilena Isabella , Abruzzese Matteo , Thorat Sanjay , Calcagno Elena , Bonaccorso Francesco 
Published: December 2023

AbstractState‐of‐the art Electrochemical Double‐Layer Capacitors (EDLCs) usually extend their operating electrochemical stability window (ESW) by means of organic electrolytes, or highly concentrated aqueous (water‐in‐salt) electrolytes hindering parasitic water splitting reactions. Unfortunately, organic solvents and high concentrations of ions penalize the dielectric constant of the electrolyte, hence the capacitive performance. We suggest here a new concept of cost‐effective and sustainable aqueous electrolytes based on concentrated amino acid water solutions with a dielectric permittivity much higher than pure water, unlocking the capacitive performance of aqueous EDLC references. Amino acids are natural zwitterionic molecules with a large separation between the positive and negative moiety, leading to huge dipoles with excellent dielectric properties. Some of them (e. g., lysine and proline), have a solubility
10 m at ambient temperature. With an experimental characterization we prove that aqueous EDLCs based on electrolytes obtained with L‐ lysine or L‐proline added to 2 M NaNO3 solution have +50 % of gravimetric capacitance enhancement at low specific currents (0.1 A/g) compared to a reference device based on 2 M NaNO3 electrolyte without amino acids. A theoretical model suggests that this performance may be further enhanced by increasing the ionic accessibility of commercially available active materials, with porosity optimized to the size of amino acid ions.
Mercaptosilane Engineered Interface with Surface‐Preferred Crystal Plane for High‐Performance Zn Anode
Authors: Li Guo‐Xian , Zhao Zhen , Yu Wei , Meng Chui‐Zhou , Guo Shi‐Jie 
Published: December 2023

AbstractZn‐ion battery (ZIB) has drawn huge attentions as a prospective energy storage system for the next generation, but dendrite and side reaction issues related to Zn have limited their potential applications. Here, a combined approach involving the modification of surface texture and the implementation of a passivation layer is proposed to tackle the problem. A zinc‐silane composite layer is coated on (002)‐preferred Zn (ZSi@Zn) by selective acid etching, concomitant with the hydrolysis of Mercaptosilane. The preferred (002) crystal plane, in conjunction with the zinc‐silane composite layer, leads in integrated interfacial transport and deposition control. As a result, the ZSi@Zn electrode has dramatically increased stability and uniform Zn deposition behavior. Remarkably, it exhibits a Coulombic efficiency of approximately 99.4 %, a long lifespan of around 3000 hours at the current density of 1 mA cm−2 with a capacity of 0.5 mAh cm−2. The excellent reversibility of zinc persists with current densities of 2, 5, and 10 mA cm−2. Furthermore, Zn‐MnO2 battery constructed with ZSi@Zn also delivers excellent performance, manifesting a capacity retention of 88.4 % after 4000 cycles.
Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma
Authors: Liu Weiren , Wang Huqiang , Zhao Qianfu , Tao Chenyang , Qu Weifeng , Hou Yushan , Huang Run , Sun Zimei , Zhu Guiqi , Jiang Xifei , Fang Yuan , Gao Jun , Wu Xiaoling , Yang Zhixiang , Ping Rongyu , Chen Jiafeng , Yang Rui , Chu Tianhao , Zhou Jian , Fan Jia , Tang Zheng , Yang Dong , Shi Yinghong 
Published: December 2023

AbstractBackgroundIntrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.MethodsWe performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.ResultsThree metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling.ConclusionVia multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.