bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered functional connectivity patterns between medial parietal and occipital in mild cognitive impairment during motion detection tasks
Authors: Gu Ming , Deng Jinxian , Sun Boxin , Kavcic Voyko , Li Tongtong , Giordani Bruno ,   Michigan Alzheimer's Disease Research Center
Published: January 2025

AbstractBackgroundPatients with cognitive impairment are likely to suffer from weakening of functional connectivity between certain brain regions, which may often be accompanied by increased connectivity between some other regions, the latter of which may reflect the compensatory mechanisms of the brain. In this EEG‐based study, we investigate the differences in functional connectivity between persons with normal cognition (NC) and MCI patients in motion detection tasks.MethodOur research focuses on task‐based EEG (64‐channel) acquired at Wayne State University, where participants with subjective cognitive complaints were asked to perform a motion direction discrimination task. The current dataset includes 56 consensus‐diagnosed, community‐dwelling African Americans (ages 60‐90 years, 28 Normal Cognitions (NC) and 28 MCI patients) recruited through the Wayne State Institute of Gerontology and Michigan Alzheimer’s Disease Research Center.We evaluated the functional connectivity at different time periods of the motion‐detection task across all the possible EEG region pairs using Pearson Correlation of the current source density (CSD). For each task trial, the successive time periods being examined included: (i) Pre‐Task resting‐state, (ii) Stimulus Onset to Go/NoGo indication, (iii) Go (or NoGo) indication to Motion‐Stop, (iv) Button‐Press period, (v) Post‐task resting‐state.ResultsOur analysis indicates that when the full band CSD signals were considered, MCI showed statistically significant (p‐value < 0.05) and increased functional connectivity between MP↔Occ in all the time periods during the motion task. In comparison, the Beta band, which is believed to be related to attentional deficits in the visual performance among older persons, showed similar trends with the full band, and consistent and statistically significant increased functional connectivity between MP and PCC were observed in the Button‐Press period across all frequency bands.ConclusionOur result suggests that MCI participants compensated for impaired connectivity in specific region pairs (see Figure 3) during the motion direction discrimination task by increasing the functional connectivity between MP and Occ to achieve comparable behavioral results to NC, and this may also be a particular indicator associated with MCI and AD pathology.Funding: NSF‐2032709/Li; NIH‐1R21AG046637‐01A1/Kavcic and NIH‐1R01AG054484‐01A1/Kavcic; NIH‐P30AG072931/Paulson; NIH‐P30AG024824/Yung.
Proteogenomic Evaluation of Cerebrospinal Fluid in Alzheimer's Disease
Authors: Puerta Raquel , García‐González Pablo , de Rojas Itziar , Olivé Clàudia , García‐Gutiérrez Fernando , Sotolongo‐Grau Oscar , Smets Bart , Emon Asif , Sung Yun Ju , Frikke‐Schmidt Ruth , Marchant Natalie L , Lambert Jean‐Charles , Valero Sergi , Marquié Marta , Ramirez Alfredo , Cruchaga Carlos , Fernández Victoria , Cano Amanda , Boada Mercè , Socorro Alfredo Cabrera , Ruiz Agustin 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is a complex disorder with a strong genetic component, yet many genetic risk factors remain unknown. Integrating genome‐wide association studies (GWAS) and high‐throughput proteomic platforms is a useful strategy to evaluate protein quantitative trait loci (pQTLs) and to detect candidate genes and pathways involved in AD. Due to the novelty of these techniques, the identification of reliable protein measures through a comprehensive quality control is mandatory.MethodWe researched the cerebrospinal fluid (CSF) proteome using the SOMAscan 7k (7289 proteins), and the Olink Explore (2943 proteins) platform in the Ace Alzheimer Center Barcelona CSF Cohort. To assess reproducibility and reliability of proteomic measures, we analysed 1) intra‐platform correlation of two independent SOMAscan assays using two aliquots of the same sample, and 2) inter‐platform correlation between SOMAscan and Olink techniques. We also explored associations of highly reliable proteins with the AD Polygenic risk score (PRS) and the conversion to AD dementia. Additionally, we have performed an extensive pQTLs mapping of the SOMAscan platform and analysed pQTLs of significant proteins linked to disease progression.ResultOur results revealed 2469 proteins with high intra‐platform correlation (rho≥0.5), selected as candidates for further analysis. Moreover, over 600 proteins demonstrated strong inter‐platform correlation, reinforcing their robustness. Extending our analysis to the entire CSF cohort (n=1322), we identified 85 proteins (Padj.<0.05) associated with the AD‐PRS. Additionally, 93 significant proteins were linked with conversion to AD dementia. Strikingly, these conversion‐associated proteins exhibited 89 genome‐wide significant pQTLs in the genome, with more than 47% of the genetic signals localized within the APOE‐rs429358 locus.ConclusionOur findings emphasize the importance of reliability assessment of highly multiplexed proteomic panels. Using robust measures, we identified significant proteins related to AD genetic risk and disease progression. These insights deepen the AD pathogenesis understanding, expand future research and therapeutic interventions.
Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study
Authors: Hu He‐Ying , Hu Hao , Yu Jin‐Tai 
Published: January 2025

AbstractBackgroundThe heart‐brain connection has been proposed to correlate cardiac disorders with brain health. However, the associations between subclinical alterations in cardiac structure or function and Alzheimer's disease (AD) pathologies haven't been fully elucidated. This study aimed to delineate the interrelationships between the subclinical alterations in the left heart, cerebrospinal fluid (CSF) AD biomarkers, and cognition.MethodMultiple linear regression analyses were conducted in 1,244 cognitively normal participants (mean age=65.5 years; 43% female) who had measurements of the left heart on echocardiograms (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers. Covariates included sociodemographic variables, lifestyle or other cardiovascular characteristics, and apolipoprotein E4 status. The mediating effects of AD pathology on heart‐cognition relationships were examined. Besides, differences in the cardiac parameters across the ATN categories were tested using ANOVA and logistic regression models.ResultLA and LV enlargement (captured by increased diameters and volumes) and LV hypertrophy (captured by increased interventricular septal or posterior wall thickness and ventricular mass) were significantly associated with higher CSF levels of phosphorylated (p)‐tau and total (t)‐tau, as well as poorer cognitive function. Tau pathologies mediated the heart‐cognition relationships. Besides, left heart parameters were higher in stage 2 and suspected non‐Alzheimer's pathology groups than in healthy controls. Moreover, the accumulation of cardiac alterations further magnified their damage to the brain.ConclusionThese findings suggested the close associations of subclinical cardiac changes with tau hyperphosphorylation, neurodegeneration and cognitive dysfunction. This study provided a comprehensive insight into the left heart condition and its impact on AD pathologies. The echocardiographic measurements of the left heart might help to identify the patients at risk of AD continuum, and we should early monitor the cardiac alterations in older adults to prevent dementia or AD.
Plasma biomarkers in a cohort of cases with dementia and in cognitively preserved nonagenarians
Authors: Gómez‐Tortosa Estrella , Agüero Pablo , Gonzales Alicia Ruiz , Wagner Sonia , Mahillo Ignacio , Ruiz Andrea , Sainz María José , Téllez Raquel , Cremades‐Jimeno Lucía , Sanchez‐Juan Pascual 
Published: January 2025

AbstractBackgroundRecent reports support the use of plasma biomarkers of neurodegeneration and neuroinflammation, as determined through ultrasensitive single molecular arrays (SIMOA), to screen and diagnose patients with dementia. However, their translation to clinical settings requires further studies.MethodsWe evaluated plasma samples from 186 individuals including 72 patients with AD (supported by CSF biomarkers consistent with an A+T+N+ classification scheme), 44 with confirmed FTD, 48 cognitively intact nonagenarians, and 22 controls (ages 40‐83 years). We measured AD core biomarkers (Abeta40, Abeta42, total tau and p‐tau181), neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) using SIMOA with Quanterix assays. In cases with dementia we correlated AD plasma biomarkers with those in CSF, obtained by Lumipulse G600II immunoassay. We calculated the best plasma cutoff values for each biomarker to discriminate among AD, FTD and cognitively preserved individuals.ResultsAs regards AD core biomarkers, AD cases showed lower Abeta42/Abeta40 ratio as compared to FTD cases and controls (p<0.001), and higher p‐tau (p=0.06 vs FTD, p=0.007 vs controls). These two biomarkers also showed a significant correlation with CSF values (Spearman p>0.001). GFAP was significantly elevated in dementia cases and nonagenarians as compared to controls with the following gradient: nonagenarians (median=344) > AD (314)> FTD (225); the same occurs for NFL with the following gradient: nonagenarians (median=41)> FTD (39.4) > AD (20). In the distinction between FTD and AD, plasma NFL showed better accuracy (AUC 0.80) than Abeta42/Abeta40 ratio (AUC 0.76), GFAP (AUC 0.68), and p‐tau (AUC 0.66). In cognitively preserved nonagenarians Abeta42 was significantly higher than in AD cases (p=0.001) and controls (p=0.01), tau and p‐tau was higher than controls but with no significant differences, while both NFL and GFAP were in the highest values of the four groups.ConclusionsIn this single‐center clinical cohort we confirm the different patterns of plasma AD core biomarkers in AD and FTD cases, as well as an opposite pattern of elevation regarding NFL and GFAP. Cognitively preserved nonagenarians have positive degeneration and inflammation biomarkers supporting resilience rather than resistance to AD.
Profiling Peripheral Blood Lymphocytes in Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Low Yi Ling Clare , Sun Jiaqi , Huang Xin , Almeida Catarina F , Gu Ben J , Kagawa Yoshiteru , Masters Colin L. , Jin Liang , Pan Yijun 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD), a major gap remains in the understanding of how the interplay between peripheral and central immune systems drives neuroinflammation and disease progression. More recently, the concept of brain lymph drainage has sparked interest as it may shed light on how the dynamics of T cell interactions contribute to AD. Our preliminary study aims to characterize alterations in the peripheral blood lymphocyte population among individuals with AD‐dementia and mild cognitive impairment (MCI), as compared with cognitively unimpaired (CU) individuals.MethodThe peripheral blood lymphocyte population of 142 participants (AD‐dementia=34, MCI=47, CU=63) recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study was profiled. Peripheral blood samples were collected for flow cytometry analysis. Cell surface markers facilitated the identification of various B and T cell populations including CD19+ pan B cells, CD4+ helper T cells, CD8+ cytotoxic T cells, CD4+CD25+CD127‐ regulatory T cells, CD4+CD8+ double positive T cells, and TCRγδ+ T cells, further categorized into subsets of CD4‐CD8‐, CD4‐CD8+ and CD4+CD8‐ TCRγδ+ T cells.ResultThe study revealed a lower percentage of CD4+CD25+CD127‐ regulatory T cells in the AD‐dementia group compared to the CU group (P=0.034, AD=6.89±1.83, CU=8.27±2.21). Significant intergroup differences were identified in the CD4+CD8+ double positive T cell population (P=0.0363), with the MCI group displaying the highest levels (0.60±0.34), followed by the AD‐dementia (0.47±0.24) and CU group (0.42±0.23). Additionally, TCRγδ+ T cells were found to be elevated in the AD‐dementia group when compared with the CU group (P=0.0023, AD=15.4±14.4, CU=7.70±9.51). Intergroup variations were also observed in the subsets of CD4+CD8‐TCRgd+ T cells (P=0.0002) and CD4‐CD8+TCRgd+ T cells (P=0.0004). However, no significant differential changes were found between the groups for CD19+ pan B (P=0.24), CD4+ helper T (P=0.29), and CD8+ cytotoxic T (P=0.56) cell populations.ConclusionThis preliminary analysis highlights disease status‐associated changes in the peripheral blood lymphocyte profile, offering potential insights into the role of peripheral immunity in AD pathology. Further research targeting alterations in the peripheral blood lymphocyte profile is warranted to uncover novel biomarkers, enabling early detection or prediction of disease severity/progression of AD.
Trimethylamine‐N‐Oxide regulates cognitive function in Alzheimer’s Disease patients and mice model through brain‐gut‐microbiota axis
Authors: Zhang Wenbo , Lü Yang 
Published: January 2025

AbstractBackgroundThe regulatory role of Trimethylamine‐N‐oxide (TMAO) for cognition from the perspective of microbiota‐gut‐brain (MGB) axis in AD remains unclear.MethodIn clinical cohort study for effects of 24‐week computerized cognitive training (CCT), registered on clinicaltrials.gov (NCT06094452), plasma TMAO levels were quantified using ELISA in MCI (n=39) and mild AD patients (n=35). Correlation analyses were conducted to assess the relationship between changes in TMAO levels and cognitive function (ADAS‐cog score) and gut microbiota indices. In animal model experiments, C57/BL6 aged mice and APP/PS1 transgenic mice were administrated by water feeding with 1.2% TMAO for 16 weeks and 1.0% of its inhibitor 3,3‐Dimethyl‐1‐butanol (DMB) for 8 weeks. TMAO levels in plasma and cerebrospinal fluid (CSF) were measured by ELISA. Cerebral blood flow (CBF) activation was detected by a laser speckle imaging system. Cognitive behavior was evaluated using Morris Water Maze test. The expressions of BBB function proteins (ZO‐1, Occludin, and PDGFRβ,) and neuroinflammatory markers (HMGB1 and IL‐1β) were detected by western blotting. The deposition of β‐amyloid (Aβ) plaques and neuronal survival in hippocampus were visualized by histochemical and Nissl staining.ResultTMAO was significantly increased in plasma of AD patients. After CCT intervention, TMAO was significantly decreased in the CCT group, and this decrease was positively correlated with ADAS‐cog (r=0.549), and negatively correlated with Shannon evenness (r= ‐0.372). TMAO changes were also negatively correlated with the relative abundance change of Roseburia (r=‐0.443), Lachnospiraceae_UCG‐004 (r=‐0.392), and Lactobacillus (r=0.480), while positively correlated with Ruminococcus_torgues (r=0.443), Fusobacterium (r=0.484) and Herbasporillum (r=0.365). In animal models, TMAO was increased in the plasma and CSF of APP/PS1 mice. After supplemented with 1.2% TMAO, the cognitive performances of C57 and APP/PS1 mice were significantly impaired. The activation amplitude of CBF was decreased, and the expression of BBB function proteins (ZO‐1, Occludin, and PDGFRβ) were significantly decreased. The expressions of neuroinflammation marker HMGB1 and IL‐1β were significantly increased; the accumulation of Aβplaques was increased with decreased neuronal survival. Circulating level of TMAO was decreased after DMB intervention, which showed cognitive protection effects.ConclusionTMAO may be a novel biomarker that regulates cognition of AD through MGB axis.
Critical Path for Alzheimer’s Disease (CPAD) Consortium: Data‐Driven Solutions for Clinical Trial Design and Informed Decision Making
Authors: Sivakumaran Sudhir , Priest Eileen , Lau Corissa , Irizarry Michael C. , Karten Yashmin 
Published: January 2025

AbstractBackgroundTo help improve the Alzheimer’s disease (AD) therapeutics research and development process, the Critical Path for Alzheimer’s Disease (CPAD) Consortium at the Critical Path Institute (C‐Path) provides a neutral framework for the drug development industry, regulatory agencies, academia, and patient advocacy organizations to collaborate. CPAD’s extensive track record of developing regulatory‐grade quantitative drug development tools motivates sponsors to share patient‐level data and neuroimages from clinical trials. CPAD leverages these data and uses C‐Path’s core competencies in data management and standardization, quantitative modeling, and regulatory science to develop tools that help de‐risk decision making in AD drug development.MethodClinical data are curated, standardized, and aggregated into analysis subsets, which are used to develop disease progression models that form the basis for clinical trial simulation (CTS) tools. Such tools help optimize patient and endpoint selection, and the design of efficacy studies. CPAD’s database includes raw neuroimages from contemporary datasets, which are used to lead two pre‐competitive efforts, in collaboration with leading academic and industry experts, to 1) test and validate a tau‐PET quantification method that harmonizes derived measures across tracers and cohorts, and 2) explore and evaluate the readiness of tau‐PET as a surrogate marker in AD drug development to support accelerated drug approval.ResultAs of November 2023, CPAD’s clinical trial repository contains 73 studies with over 100,000 individual de‐identified patient records, with a rich source of key AD biomarkers (biofluids and imaging). Different linear and non‐linear mixed effects models have been fit based on relevant biomarker combinations, characterizing the time course of clinically relevant outcome measures. To harmonize tau‐PET quantification, two different methods (a Centiloid‐like approach and a Joint Propagation model) were tested and validated across multiple tracers, cohorts and studies. A data and research plan has been drafted to explore and evaluate the readiness of tau‐PET as a surrogate marker in AD.ConclusionThe precompetitive collaboration by CPAD is fundamental to the generation of actionable quantitative drug development tools for accelerating and advancing AD drug development and building consensus among stakeholders that provide confidence to sponsors for the adoption of the tools.
Automated linguistic and acoustic measures of verbal fluency as neurocognitive markers of mild cognitive impairment
Authors: Pérez Gonzalo Nicolás , Ponferrada Joaquín , Ferrante Franco Javier , Caro Iván , Bisé Joaquín Valdez , Migeot Joaquín , Welford Alejandro Sosa , Olavarria Loreto , Pelle Patricia , Chonchol Andrea Slachevsky , Ferrer Luciana , Garcia Adolfo M. 
Published: January 2025

AbstractBackgroundVerbal fluency tasks are routinely employed in screening for mild cognitive impairment (MCI). Yet, traditional outcome measures focus on the number of valid responses, failing to reveal which specific semantic memory dimensions may be altered and limiting analyses to univariate methods. Building on recent findings on Alzheimer’s disease, we employed automated methods to establish which linguistic and speech timing features better discriminate MCI patients from healthy controls (HCs), including machine learning analyses, comparisons with standard neuropsychological tests, and brain‐behavior correlations.MethodWe recruited 106 native Spanish speakers (52 with MCI, 54 HCs), who completed phonemic and semantic fluency tasks as well as standard tests of attention (Trail Making Test‐A) and episodic memory (Free and Cued Selective Reminding Test). Responses in the fluency tasks were audio‐recorded and transcribed for automatic extraction of word properties (granularity, frequency, phonological neighborhood, word length, imageability, familiarity) and speech timing features (number of syllables, pauses, pause duration, phonation time, articulation rate, average syllable duration). These variables were compared between groups through a generalized linear model (GLM, with standard cognitive test scores as covariates) and fed into a binary classifier for subject‐level discrimination. Structural and functional brain measures were obtained from 63 participants and subjected to voxel‐based morphometry and seed‐to‐voxel resting‐state connectivity analyses. Correlations between behavioral and brain features were examined via multiple regressions.ResultGLM analysis revealed significant group differences in specific word properties (granularity, frequency, word length, imageability), but not in speech timing features. Subject‐level classification was better when based on word properties (AUC = 0.72) than on speech timing features (AUC = 0.63), with maximal discrimination upon combining both dimensions (AUC = 0.78). MCI patients exhibited atrophy left temporal atrophy and altered connectivity between the right parahippocampus and fronto‐posterior cortical regions. Word frequency was negatively correlated with insular volume and granularity was positively correlated with the volume of fusiform and parahippocampal regions.ConclusionAutomated analyses of word properties and timing features in verbal fluency tasks offer novel insights into cognitive decline, surpassing traditional tests in identifying MCI. Their widespread implementation could inaugurate a promising avenue to establish scalable markers of the condition.