Browsing by Author "Kueider-Paisley, Alexandra"
Now showing 1 - 9 of 9
Results Per Page
Sort Options
Item Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers(Elsevier, 2019-02) Nho, Kwangsik; Kueider-Paisley, Alexandra; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Jia, Wei; Xie, Guoxiang; Ahmad, Shahzad; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.Item Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers(American Medical Association, 2019-07) Nho, Kwangsik; Kueider-Paisley, Alexandra; Ahmad, Shahzad; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; van Duijn, Cornelia; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineImportance: Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD. Objective: To examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD. Design, Setting, and Participants: In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019. Exposures: Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables. Main Outcomes and Measures: Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography. Results: Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], -0.465 [0.180]; P = .02 for memory composite score; β [SE], -0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], -0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], -0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers). Conclusions and Relevance: Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.Item Bile acids targeted metabolomics and medication classification data in the ADNI1 and ADNIGO/2 cohorts(Nature Research, 2019-10-17) St. John-Williams, Lisa; Mahmoudiandehkordi, Siamak; Arnold, Matthias; Massaro, Tyler; Blach, Colette; Kastenmüller, Gabi; Louie, Gregory; Kueider-Paisley, Alexandra; Han, Xianlin; Baillie, Rebecca; Motsinger-Reif, Alison A.; Rotroff, Daniel; Nho, Kwangsik; Saykin, Andrew J.; Risacher, Shannon L.; Koal, Therese; Moseley, M. Arthur; Tenenbaum, Jessica D.; Thompson, J. Will; Kaddurah-Daouk, Rima; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; Radiology and Imaging Sciences, School of MedicineAlzheimer’s disease (AD) is the most common cause of dementia. The mechanism of disease development and progression is not well understood, but increasing evidence suggests multifactorial etiology, with a number of genetic, environmental, and aging-related factors. There is a growing body of evidence that metabolic defects may contribute to this complex disease. To interrogate the relationship between system level metabolites and disease susceptibility and progression, the AD Metabolomics Consortium (ADMC) in partnership with AD Neuroimaging Initiative (ADNI) is creating a comprehensive biochemical database for patients in the ADNI1 cohort. We used the Biocrates Bile Acids platform to evaluate the association of metabolic levels with disease risk and progression. We detail the quantitative metabolomics data generated on the baseline samples from ADNI1 and ADNIGO/2 (370 cognitively normal, 887 mild cognitive impairment, and 305 AD). Similar to our previous reports on ADNI1, we present the tools for data quality control and initial analysis. This data descriptor represents the third in a series of comprehensive metabolomics datasets from the ADMC on the ADNI.Item Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease(Cell Press, 2020-11-17) Baloni, Priyanka; Funk, Cory C.; Yan, Jingwen; Yurkovich, James T.; Kueider-Paisley, Alexandra; Nho, Kwangsik; Heinken, Almut; Jia, Wei; Mahmoudiandehkordi, Siamak; Louie, Gregory; Saykin, Andrew J.; Arnold, Matthias; Kastenmüller, Gabi; Griffiths, William J.; Thiele, Ines; Kaddurah-Daouk, Rima; Price, Nathan D.; Radiology and Imaging Sciences, School of MedicineIncreasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.Item Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease(Springer Nature, 2022-10-08) Baloni, Priyanka; Arnold, Matthias; Buitrago, Luna; Nho, Kwangsik; Moreno, Herman; Huynh, Kevin; Brauner, Barbara; Louie, Gregory; Kueider-Paisley, Alexandra; Suhre, Karsten; Saykin, Andrew J.; Ekroos, Kim; Meikle, Peter J.; Hood, Leroy; Price, Nathan D.; The Alzheimer’s Disease Metabolomics Consortium; Doraiswamy, P. Murali; Funk, Cory C.; Hernández, A. Iván; Kastenmüller, Gabi; Baillie, Rebecca; Han, Xianlin; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineDysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.Item Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease(Wiley, 2023) Chang, Rui; Trushina, Eugenia; Zhu, Kuixi; Zaidi, Syed Shujaat Ali; Lau, Branden M.; Kueider-Paisley, Alexandra; Moein, Sara; He, Qianying; Alamprese, Melissa L.; Vagnerova, Barbora; Tang, Andrew; Vijayan, Ramachandran; Liu, Yanyun; Saykin, Andrew J.; Brinton, Roberta D.; Kaddurah-Daouk, Rima; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; Radiology and Imaging Sciences, School of MedicineIntroduction: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. Discussion: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.Item Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex-Dependent Manner(Wiley, 2024) Chen, Tianlu; Wang, Lu; Xie, Guoxiang; Kristal, Bruce S.; Zheng, Xiaojiao; Sun, Tao; Arnold, Matthias; Louie, Gregory; Li, Mengci; Wu, Lirong; Mahmoudiandehkordi, Siamak; Sniatynski, Matthew J.; Borkowski, Kamil; Guo, Qihao; Kuang, Junliang; Wang, Jieyi; Nho, Kwangsik; Ren, Zhenxing; Kueider-Paisley, Alexandra; Blach, Colette; Kaddurah-Daouk, Rima; Jia, Wei; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Metabolomics Consortium (ADMC); Radiology and Imaging Sciences, School of MedicineSex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.Item Serum metabolites associated with brain amyloid beta deposition, cognition and dementia progression(Oxford University Press, 2021-07-02) Nho, Kwangsik; Kueider-Paisley, Alexandra; Arnold, Matthias; MahmoudianDehkordi, Siamak; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineMetabolomics in the Alzheimer's Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer's disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer's disease. We examined 140 serum metabolites and their associations with brain amyloid-β deposition, cognition and conversion from mild cognitive impairment to Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative. Processed [18F] Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-β accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-β deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-β accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-β deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer's disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer's disease as measured by brain amyloid-β deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-β in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer's disease or if they are biomarkers for systemic changes during preclinical phases of the disease.Item Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome(Springer Nature, 2020) Arnold, Matthias; Nho, Kwangsik; Kueider-Paisley, Alexandra; Massaro, Tyler; Huynh, Kevin; Brauner, Barbara; MahmoudianDehkordi, Siamak; Louie, Gregory; Moseley, M. Arthur; Thompson, J. Will; St. John-Williams, Lisa; Tenenbaum, Jessica D.; Blach, Colette; Chang, Rui; Brinton, Roberta D.; Baillie, Rebecca; Han, Xianlin; Trojanowski, John Q.; Shaw, Leslie M.; Martins, Ralph; Weiner, Michael W.; Trushina, Trushina; Toledo, Jon B.; Meikle, Peter J.; Bennett, David A.; Krumsiek, Jan; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Kastenmüller, Gabi; Radiology and Imaging Sciences, School of MedicineLate-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.