bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fosgonimeton, a Small‐Molecule Positive Modulator of the HGF/MET System, Attenuates Amyloid‐β – Mediated Toxicity in Primary Neuron Culture
Authors: Reda Sherif , Wu Wei , Helton Leah , Taylor Robert W , Johnston Jewel L , Church Kevin J. 
Published: December 2023

AbstractBackgroundPositive modulation of the hepatocyte growth factor (HGF)/MET system may represent a promising therapeutic strategy for Alzheimer’s disease (AD). Downstream effectors of HGF/MET, such as AKT or ERK, have been shown to activate pro‐survival signaling cascades that counteract pathological components of AD including excitotoxicity, mitochondrial dysfunction, oxidative stress, and protein aggregation. We have previously that fosgonimeton, a small molecule positive modulator of the HGF/MET system, elicits broad neuroprotective effects (Johnston et. al, 2022). Herein, we investigate the mechanism of action by which fosgonimeton induces neuroprotective effects in beta‐amyloid and glutamate‐challenged primary cortical neurons.MethodPrimary rat cortical neurons were treated with the active metabolite of fosgonimeton (fosgo‐AM), challenged with beta‐amyloid (Aβ1‐42; 15 µM) for 24 hours, and co‐immunostained for microtubule‐associated protein‐2 (MAP‐2) and phospho‐tau (AT100). Immunofluorescence analyses were used to determine neuronal survival, neurite network integrity (total neurite length), and phospho‐tau levels. In a separate model, rat cortical neurons were treated with fosgo‐AM and challenged with glutamate (20 µM) for 24 hours, and immunostained for MAP‐2 to determine neuronal survival and neurite network. To elucidate the mechanism of neuroprotection, protein analyses via western blot and homogenous time‐resolved fluorescence were conducted to assay HGF/MET downstream signaling pathways. In addition, the effect of fosgo‐AM on mitochondrial membrane potential (MMP) was assessed in primary cortical neuron culture via fluorescent MMP dye.ResultFosgo‐AM treatment significantly improved survival of cortical neurons, protected neurite networks, and reduced tau hyperphosphorylation after injury with Aβ1‐42. Additionally, fosgo‐AM reduced glutamate‐mediated cortical neuron death and neurite degeneration. Analyses of downstream signaling effects indicate that the neuroprotective effects of fosgo‐AM treatment may, in part, be the result of activation of AKT signaling and subsequent rescue of mitochondrial membrane potential, thereby reducing protein pathology and oxidative stress.ConclusionOur in vitro data demonstrate the address pathological of AD reduce tau . neuroprotective effects of fosgonimeton, in addition to its neurotrophic and pro‐cognitive effects in preclinical models, highlight its therapeutic potential to interrupt disease progression and restore neuronal health. Fosgonimeton is currently in clinical for mild‐to‐moderate AD (NCT04488419; NCT04886063).
Deep quantitative proteomics analysis of the brain vasculature in Alzheimer’s disease and related tauopathies.
Authors: Wojtas Aleksandra 
Published: December 2023

AbstractBackgroundDysfunction of neurovascular unit represents a major pathological hallmark of Alzheimer’s disease (AD) and age‐related cognitive impairment. Diminished blood flow and blood‐brain barrier breakdown have been linked to the accumulation of amyloid‐b (Ab) peptide in brain parenchyma and cerebral blood vessels. Additionally, cerebrovascular dysfunction has been associated with tau pathology in primary tauopathies, including progressive supranuclear palsy (PSP) where amyloid deposition is not present. Despite the significance of brain vasculature in maintaining the proper neuronal function, the proteomic profiles of cerebrovasculature remain poorly characterized.MethodsHere, for the first time we implemented a tandem mass tag spectrometry (TMT‐MS) approach to thoroughly examine proteomic features of human cerebrovasculature from postmortem brain tissues from AD, PSP, and non‐demented control individuals (N = 20‐24 cases/diagnosis) from the University of Pennsylvania School of Medicine Brain Bank. The human cerebrovasculature was isolated from frontal cortex using density‐mediated separation to purify blood vessels from parenchymal components.ResultsThe quantification of over 9,800 proteins allowed us to generate deep TMT protein co‐expression network consisting of 93 communities of proteins displaying wide biological heterogeneity associated with diverse brain pathologies. Importantly, the comparison of vascular proteome with proteomic data obtained from bulk brain tissues from the same individuals gave us a unique opportunity to interrogate the relationship and preservation between different data sets. We also explored how candidate gene products that confer the risk for AD or PSP map to the discovered protein modules.ConclusionsIn summary, by taking advantage of our network‐driven approach we nominated pathways strongly correlated with AD‐like neuropathological traits and vascular biology that could provide the foundation for our understanding of the mechanisms governing AD‐linked breakdown of BBB, dysregulation of the cerebral blood flow, and pathological accumulation of protein aggregates in human vasculature.
Apolipoprotein (APOE4) allele as a predictor for Amygdala structure and Anxiety in normal aging‐ Results from the Triple‐A (Amygdala, Anxiety, and Ageing) study
Authors: Issac Thomas Gregor , Sundarakumar Jonas S. , Stezin Albert , Malo Palash Kumar 
Published: December 2023

AbstractBackgroundApolipoprotein E4 (APOE4) gene is an important risk factor based on available literature for late onset Alzheimer’s dementia and its effect on normal brain aging in Low and Middle‐income countries has been less studied. The evolutionary benefit that APOE4 confers against various infections during the younger age versus the vulnerability it offers that predisposes to the development of late‐onset cognitive decline is quite exciting but very less studied. We attempt to look into the effects of APOE4 carrier status and its influence on Amygdala structure and as an independent predictor for the development of late‐life anxiety symptoms.MethodThe subjects were recruited from the Tata Longitudinal Study of Ageing (TLSA) cohort, which is an Urban cohort wherein cognitively healthy participants ≥45 years, evaluated for baseline clinical cognitive, genetic, and imaging studies and followed up annually. About 102 participants whose APOE4 genotyping were done were included in this study and compared with their imaging characteristics especially looking into the amygdaloid volumes. Data was analyzed using SPSS v.24ResultMore than half of the participants were females (52%). The APOE4 carrier status (homozygous or heterozygous to APOE4 allele) was present in 51% of the individuals, and only 2.2% of the subjects had overt anxiety symptoms. The mean age of females were 63.89土9.6 and Males 64.82 土 9.3 years, respectively. With normalized imaging data, it was found that males had significantly higher left and right amygdaloid volumes than females(P<0.001) irrespective of the carrier status, and when the Hindi Mental Status Examination (HMSE) scores were considered as an outcome measure, there was a significant reduction in the Right amygdala volumes in the carriers versus non carriers.ConclusionAmygdala is an integral part of the limbic system mediating emotions tagged to cognition, and its structure is likely modulated by the APOE4 carrier status. It could likely impact global cognition even when there is no significant difference in neuropsychological test scores between the carriers and non‐carriers in a cohort of cognitively normal individuals. However, ApoE4 carrier status does not seem to predict anxiety or depression early in cognitively healthy individuals, especially among the Indian population.
The investigation of hippocampal free‐water as a biomarker for cognitive impairment and decline in older adults
Authors: Sathe Aditi , Shashikumar Niranjana , Moore Elizabeth E. , Pechman Kimberly R. , Landman Bennett A. , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. , Archer Derek B 
Published: December 2023

AbstractBackgroundWhile diffusion MRI derived free‐water (FW) metrics have shown promise in predicting cognitive impairment and decline in aging and Alzheimer’s disease (AD), it is unclear whether hippocampal FW metrics would be superior to traditional structural neuroimaging biomarkers (i.e., hippocampal volume, AD Schwarz Signature, AD McEvoy Signature). We examined the relationships between hippocampal FW metrics and traditional neuroimaging biomarkers with longitudinal memory and executive function.MethodVanderbilt Memory & Aging Project participants [n = 298, age at baseline: 73 ± 7 years, 40% mild cognitive impairment (MCI)] underwent longitudinal neuropsychological assessment and brain MRI over a 7 year follow‐up (mean: 3 ± 2 years) period. Structural MRI was used to quantify hippocampal volume in addition to Schwarz and McEvoy signatures. Diffusion MRI in conjunction with the FW elimination technique was used to quantify hippocampal FW and FW‐corrected fractional anisotropy (FAFWcorr). Linear regression was used to determine the association of each biomarker with baseline memory and executive function. A subsequent competitive model analysis was conducted to determine how much additional variance was provided by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein‐e4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. Additionally, linear mixed‐effects regression was used to determine the association between baseline biomarker values with longitudinal memory and executive function scores. All analyses were corrected for multiple comparisons using the FDR procedure.ResultAt baseline, all biomarkers (excluding hippocampal FAFWcorr) were significantly associated with cognitive performance (Table 1), with hippocampal FW exhibiting the most significant association for memory (pFDR = 3.92×10−6) and executive function (pFDR = 5.35×10−3). Competitive models revealed that hippocampal FW contributed the most unique variance beyond covariates for memory (ΔRadj
2 = 3.87%) and executive function (ΔRadj
2 = 1.59%). Longitudinal models (Table 2, Figure 1) largely mirrored cross‐sectional models by demonstrating that hippocampal FW was most significantly associated with longitudinal decline in memory (pFDR = 5.04×10−13) and executive function (pFDR = 6.15×10−5).ConclusionThis study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.
Astrocyte reactivity moderates the effect of education on cognitive reserve
Authors: Borelli Wyllians Vendramini , Antônio De Bastiani Marco , Bieger Andrei , Ferrari‐Souza João Pedro , Castilhos Raphael Machado , Rosa‐Neto Pedro , Zimmer Eduardo R. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundCognitive reserve and resilience account for differential susceptibility to brain aging and disease across individuals. Previous data suggest that functional connectivity among different brain areas is associated with cognitive reserve. However, its neural basis is yet unclear. In this study, we investigated the moderating effect of astrocyte reactivity in cognitive reserve.MethodCognitively unimpaired individuals who had plasma GFAP analyzed were selected from ADNI at baseline (n = 130). Years of education were used as a proxy of cognitive reserve; the Montreal Cognitive Assessment (MoCA) total score was retrieved from all individuals. A moderation analysis was performed according to the most recent framework for reserve and resilience in aging concepts. The total MoCA score was the outcome, and we investigated the moderation of plasma GFAP in the association of years of education and MoCA. Data are shown as mean+‐SD.ResultA total of 130 individuals had complete data for all variables (72.3+‐6.3 years of age; 16.36+‐2.75 years of education; 43.1% females). A significant moderating effect was found in plasma GFAP and years of education (beta = 0.004, p = 0.0006) as a predictor of total MoCA scores (Model R2 = 0.37, p < 0.0001) when correcting for age and gender. Plasma GFAP and sex were also predictors of total MOCA scores independently (p<0.001 for both). Plasma GFAP was a moderator in individuals below 18 years of education (p = 0.003), but not above 18 years of education (p = 0.9).ConclusionAstrocyte reactivity may play a potential role in the neural basis of cognitive reserve. The neuroprotective effect of astrocytes in cognitive reserve may have a ceiling effect. Further studies may investigate the importance of glial interactions with brain regions and its ability to predict cognitive changes in a longitudinal analysis.
Cognitive profiles are associated with brain morphometry years later in Hispanics/Latinos: Preliminary findings from the SOL‐INCA‐MRI study
Authors: Sapkota Shraddha , Maillard Pauline , Stickel Ariana M , Tarraf Wassim , Gonzalez Kevin A , Ivanovic Vladimir , Paredes Alejandra Morlett , Zeng Donglin , Cai Jianwen , Isasi Carmen R , Kaplan Robert C. , Lipton Richard B. , Daviglus Martha L , Testai Fernando Daniel , Lamar Melissa , Gallo Linda C , Talavera Gregory A , Gellman Marc D , Ramos Alberto R , González Hector M , Decarli Charles 
Published: December 2023

AbstractBackgroundHispanics/Latinos are the largest and most diverse ethnoracial group at high risk for Alzheimer’s disease and related dementias across the US. However, this population is largely understudied. We present preliminary findings on the association between cognitive profiles and brain morphometry measures in a large Hispanic/Latino cohort of older adults.MethodWe used a longitudinal cohort of cognitively normal older adults (n = 2028; mean baseline age = 54.19 (6.75) years, 69.5% female) from the Study of Latinos‐Investigation of Neurocognitive Aging‐Magnetic Resonance Imaging (SOL‐INCA‐MRI). First, to establish a latent memory variable, we examined confirmatory factor analysis to test loadings of four manifest variables (Spanish‐English‐Verbal‐Learning Test learning and recall, digit symbol, word frequency) at the first (2008‐2015) and second (2015‐2021) cognitive visits. Second, we examined whether tertiles of our latent cognitive score were associated with two measures of brain integrity (white matter hyperintensities [WMH] and hippocampus) measured between 2018‐2022. The brain morphometry measures were regressed independently on cognitive tertiles at both visits. Age at each visit, sex, education, Hispanic/Latino background, and cognitive‐MRI lag time were included as covariates.ResultFirst, a two‐factor latent memory profile (episodic memory and working memory) best represented our four manifest variables at both visits 1 and 2. Each tertile corresponded to low (1), intermediate (2), and high (3) performing groups. Second, increase in cognitive tertile (from low to intermediate to high) on episodic memory (β = ‐0.157, SE = 0.040, p< 0.001) and working memory (β = ‐0.192, SE = 0.043, p< 0.001) at visit 1 was associated with lower WMH. Increase in cognitive tertile on episodic and working memory at visit 2 was associated with lower WMH (β = ‐0.241, SE = 0.036, p< 0.001 and β = ‐0.260, SE = 0.043, p< 0.001, respectively) and greater hippocampus (β = 0.051, SE = 0.015, p = 0.001 and β = 0.040, SE = 0.018, p = 0.025, respectively).ConclusionOur preliminary findings showed that cognitive profiles and key brain integrity measures are associated years later in Hispanic/Latino adults. Careful monitoring of cognitive aging profiles in the Hispanic/Latino community may lead to early detection and intervention of older adults at high risk for future neurodegeneration.
Alzheimer’s disease phenotypes in human induced pluripotent stem cell‐based models of Down syndrome
Authors: Johnson Noah R , Dooling Breanna , Ahmed Md. Mahiuddin , Summers Rose , Chial Heidi J , Potter Huntington 
Published: December 2023

AbstractBackgroundBy age 40, all people with Down syndrome (DS) develop Alzheimer’s disease (AD) brain neuropathology, including Aβ plaques and neurofibrillary tangles of phosphorylated microtubule associated protein tau (MAPT), and most go on to develop early‐onset dementia. People with Down syndrome (DS) have triplication of chromosome 21 (trisomy 21) and they develop AD neuropathology due to triplication of the amyloid precursor protein gene (APP) which resides on chromosome 21. Here, we developed and characterized human induced pluripotent stem cell (hiPSC)‐derived neurons, astrocytes, microglia, and cerebral organoid (CO) models of DS and familial AD and used them to evaluate the AD‐related pathological mechanisms caused by trisomy 21.MethodWe obtained hiPSC lines derived from individuals with DS, healthy control individuals (HC), and individuals with familial AD, including duplication of APP on one chromosome (APPdup) or carrying the London mutation in APP (APPV717I). All donors had the apolipoprotein E (APOE) ε3/ε3 genotype. We generated hiPSC‐derived neurons, astrocytes, microglia, and COs using validated techniques. We evaluated the hiPSC‐derived neural cells and COs at different ages for AD‐related neuropathology, neuroinflammation, and neurodegeneration by performing RNA sequencing, immunohistochemistry, immunoblotting, and enzyme‐linked immunosorbent assay.ResultAD‐related size phenotypes characteristic of neurodegeneration were observed in DS hiPSC‐based models relative to HC models. Dysregulated gene and protein expression of APP, MAPT, and APOE, in addition to chromosome 21 genes, were also observed in DS hiPSC‐based models. In particular, neuroinflammatory markers, especially those previously shown in APOE‐related pathways, were also increased in DS models.ConclusionWe characterized new hiPSC‐based models of DS and familial AD which will be useful for identifying commonalities in disease mechanisms as well as for dissecting the roles of chromosome 21 genes other than APP. We identified several AD‐related phenotypes in hiPSC‐based DS related to neuropathology, neuroinflammation, and neurodegeneration. We expect that these hiPSC‐based models will be useful for testing therapeutics in the future to address AD in people with DS, for which there is no cure.
Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer’s disease in the EMIF‐AD Multimodal Biomarker Discovery study
Authors: Smith Rebecca G. , Imm Jennifer L , Dobricic Valerija , Sommerer Yasmine , Bos Isabelle , Vos Stephanie J. B. , Verhey Frans R.J. , Scheltens Philip , Engelborgs Sebastiaan , Frisoni Giovanni B , Blin Olivier , Richardson Jill C , Bordet Régis , Tsolaki Magda , Popp Julius , Martinez‐Lage Pablo , Lleo Alberto , Johannsen Peter , Freund‐Levi Yvonne , Lutz Frölich , Vandenberghe Rik , Wittig Michael , Frank Andre , Lovestone Simon , Streffer Johannes , Andreasson Ulf , Blennow Kaj , Visser Pieter Jelle , Zetterberg Henrik , Bertram Lars , Lunnon Katie 
Published: December 2023

AbstractBackgroundThe aim of this study was to identify DNA methylation signatures that were associated with 15 CSF biomarker measures of Alzheimer’s disease (AD) or neurodegeneration.MethodWe profiled DNA methylation in 886 blood samples from the EMIF‐AD study using the Illumina EPIC array, identifying differentially methylated loci, and regions consisting of multiple adjacent differentially methylated sites.ResultsWe identified Bonferroni‐significant differences in DNA methylation with respect to CSF t‐tau Z‐score (five loci), Aβ42 levels (one loci), YKL‐40 levels (six loci) and NFL (seven loci). Significant differentially methylated regions were identified in 13 of the 15 analyses, with overlapping regions featuring in multiple CSF measures(MX2, RHOH, ANKMY1, ZFP57) analyses, which was unsurprising given the high correlation between measures. Interestingly, we identified several regions that overlapped between the tau and amyloid (ZBTB22), tau and NFL (S100A13), NFL and neurogranin (SORD), and neurogranin and amyloid (STRA6) regional analyses.ConclusionIn this blood‐based epigenome‐wide association study of AD‐relevant CSF biomarkers we identified several interesting genomic loci and regions.
Age‐ and Sex‐Related Morphological Changes in Cerebral Blood Vessels: a 7T TOF MRA Study
Authors: Li Jiatai , Stetten George D , Schweitzer Noah , Shi Zonghua , Ibrahim Tamer , Yang Shaolin , Iordanova Bistra , Aizenstein Howard J , Wu Minjie 
Published: December 2023

AbstractBackgroundIn this study we evaluated age‐ and sex‐associated morphological changes of cerebral blood vessels using 7T Time‐of‐flight (TOF) magnetic resonance angiography (MRA).MethodOur study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole‐Brain TOF MRA images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number = 354, voxel size = 0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images (Li et al., 2023). For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter.ResultAs shown in Figure 1, we found age‐related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02). This age‐related difference is driven by small vessels (p = 0.002) rather than large vessels (p = 0.7). We also found that age is positively associated with mean voxel tortuosity (p<0.001, black line in Figure 2). Furthermore, women showed greater age‐related increase in mean arterial tortuosity, compared to men (age*sex interaction p = 0.04, Figure 2).ConclusionOur findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD‐related AD risk in women.Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N = 25). A cross‐sectional instead of longitudinal design was used in this analysis. Future study with a large balanced sample and a longitudinal design are required to confirm our findings.Reference: Li, Jiatai, et al. “VesselMapper ‐ A Robust Vessel Segmentation Algorithm for 3D Images.” Annual Meeting of the Organization for Human Brain Mapping. 2023