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1. Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex‐Dependent Manner

Author

Tianlu Chen, Lu Wang, Guoxiang Xie, Bruce S. Kristal, Xiaojiao Zheng, Tao Sun, Matthias Arnold, Gregory Louie, Mengci Li, Lirong Wu, Siamak Mahmoudiandehkordi, Matthew J. Sniatynski, Kamil Borkowski, Qihao Guo, Junliang Kuang, Jieyi Wang, Kwangsik Nho, Zhenxing Ren, Alexandra Kueider‐Paisley, Colette Blach, Rima Kaddurah‐Daouk, Wei Jia, and Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Alzheimer Disease Metabolomics Consortium (ADMC)

Subjects
alzheimer's disease, bile acid, cholesterol, mild cognitive impairment, sex difference, Science
Abstract

Abstract Sex 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.

Published
2024
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2. Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

Author

Hugo Geerts, John Wikswo, Piet H. van derGraaf, Jane P.F. Bai, Chris Gaiteri, David Bennett, Susanne E. Swalley, Edgar Schuck, Rima Kaddurah‐Daouk, Katya Tsaioun, and Mary Pelleymounter

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross‐disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior. The National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with the National Institute on Aging (NIA), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and National Center for Advancing Translational Sciences (NCATS), convened a workshop to explore and evaluate the potential of a quantitative systems pharmacology (QSP) approach to CNS drug discovery and development. The objective of the workshop was to identify the challenges and opportunities of QSP as an approach to accelerate drug discovery and development in the field of CNS disorders. In particular, the workshop examined the potential for computational neuroscience to perform QSP‐based interrogation of the mechanism of action for CNS diseases, along with a more accurate and comprehensive method for evaluating drug effects and optimizing the design of clinical trials. Following up on an earlier white paper on the use of QSP in general disease mechanism of action and drug discovery, this report focuses on new applications, opportunities, and the accompanying limitations of QSP as an approach to drug development in the CNS therapeutic area based on the discussions in the workshop with various stakeholders.

Published
2020
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3. Sets of coregulated serum lipids are associated with Alzheimer's disease pathophysiology

Author

Dinesh Kumar Barupal, Rebecca Baillie, Sili Fan, Andrew J. Saykin, Peter J. Meikle, Matthias Arnold, Kwangsik Nho, Oliver Fiehn, Rima Kaddurah‐Daouk, Alzheimer's Disease Neuroimaging Initiative, and Alzheimer Disease Metabolomics Consortium

Subjects
Alzheimer's disease, Lipidomics, Dyslipidemias, Lipid biochemistry, Mass spectrometry, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction Comorbidity with metabolic diseases indicates that lipid metabolism plays a role in the etiology of Alzheimer's disease (AD). Comprehensive lipidomic analysis can provide new insights into the altered lipid metabolism in AD. Method In this study, a total 349 serum lipids were measured in 806 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative Phase 1 cohort and analyzed using lipid‐set enrichment statistics, a data mining method to find coregulated lipid sets. Results We found that sets of blood lipids were associated with current AD biomarkers and with AD clinical symptoms. AD diagnosis was associated with 7 of 28 lipid sets of which four also correlated with cognitive decline, including polyunsaturated fatty acids. Cerebrospinal fluid amyloid beta (Aβ1‐42) correlated with glucosylceramides, lysophosphatidylcholines and unsaturated triacylglycerides; cerebrospinal fluid total tau and brain atrophy correlated with monounsaturated sphingomyelins and ceramides, in addition to EPA‐containing lipids. Discussion AD‐associated lipid sets indicated that lipid desaturation, elongation, and acyl chain remodeling processes are disturbed in AD subjects. Monounsaturated lipid metabolism was important in early stages of AD, whereas the polyunsaturated lipid metabolism was associated with later stages of AD. Our study provides several new hypotheses for studying the role of lipid metabolism in AD.

Published
2019
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4. Influence of Sex on Platelet Reactivity in Response to Aspirin

Author

Kevin A. Friede, Margaret M. Infeld, Ru San Tan, Holly J. Knickerbocker, Rachel A. Myers, Laura G. Dubois, J. Will Thompson, Rima Kaddurah‐Daouk, Geoffrey S. Ginsburg, Thomas L. Ortel, and Deepak Voora

Subjects
aspirin, platelets, sex differences, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background There are sex differences in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke. Whether this is explained by underlying differences in platelet reactivity and aspirin response remains poorly understood. Methods and Results Healthy volunteers (n=378 208 women) and patients with coronary artery disease or coronary artery disease risk factors (n=217 112 women) took aspirin for 4 weeks. Light transmittance aggregometry using platelet‐rich plasma was used to measure platelet reactivity in response to epinephrine, collagen, and ADP at baseline, 3 hours after the first aspirin dose, and after 4 weeks of daily aspirin therapy. A subset of patients underwent pharmacokinetic and pharmacodynamic assessment with levels of salicylate and cyclooxygenase‐1–derived prostaglandin metabolites and light transmittance aggregometry in response to arachidonic acid and after ex vivo exposure to aspirin. At baseline, women had increased platelet aggregation in response to ADP and collagen. Innate platelet response to aspirin, assessed with ex vivo aspirin exposure of baseline platelets, did not differ by sex. Three hours after the first oral aspirin dose, platelet aggregation was inhibited in women to a greater degree in response to epinephrine and to a lesser degree with collagen. After 4 weeks of daily therapy, despite higher salicylate concentrations and greater cyclooxygenase‐1 inhibition, women exhibited an attenuation of platelet inhibition in response to epinephrine and ADP. Conclusions We observed agonist‐dependent sex differences in platelet responses to aspirin. Despite higher cyclooxygenase‐1 inhibition, daily aspirin exposure resulted in a paradoxical attenuation of platelet inhibition in response to epinephrine and ADP over time in women but not in men.

Published
2020
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5. Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics

Author

Mohamed H. Shahin, Yan Gong, Reginald F. Frye, Daniel M. Rotroff, Amber L. Beitelshees, Rebecca A. Baillie, Arlene B. Chapman, John G. Gums, Stephen T. Turner, Eric Boerwinkle, Alison Motsinger‐Reif, Oliver Fiehn, Rhonda M. Cooper‐DeHoff, Xianlin Han, Rima Kaddurah‐Daouk, and Julie A. Johnson

Subjects
blood pressure, lipid metabolites, metabolomics, pharmacogenetics, thiazide diuretics, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundAlthough hydrochlorothiazide (HCTZ) is a well‐established first‐line antihypertensive in the United States,

Published
2018
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6. Brain region‐specific metabolic signatures of Alzheimer’s disease

Author

Richa Batra, Jan Krumsiek, Xue Wang, Mariet Allen, Maria A. Wörheide, Colette Blach, David A Bennett, Gabi Kastenmüller, Matthias Arnold, Nilufer Ertekin‐Taner, and Rima Kaddurah‐Daouk

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

7. Associations between gut microbial families and brain myelin in a human cohort

Author

Kao Lee Yang, Margo B. Heston, Akshay Kohli, Steven R Kecskemeti, Antonio González, Rob Knight, Rima Kaddurah‐Daouk, Federico E. Rey, and Barbara B. Bendlin

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

9. Bacteroides genus is associated with lower executive function in cognitively unimpaired participants

Author

Allison A Forst, Margo B. Heston, Antonio González, Nathaniel A. Chin, Robert J Przybelski, Sterling C. Johnson, Sanjay Asthana, Rob Knight, Rima Kaddurah‐Daouk, Federico E. Rey, and Barbara B. Bendlin

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

10. Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

Author

Edgar Schuck, Mary Pelleymounter, Piet van der Graaf, Rima Kaddurah-Daouk, Katya Tsaioun, John P. Wikswo, Hugo Geerts, Susanne E. Swalley, Jane P. F. Bai, David A. Bennett, and Chris Gaiteri

Subjects
Drug, media_common.quotation_subject, White Paper, Drug Development, Central Nervous System Diseases, Drug Discovery, Medicine, Animals, Humans, Pharmacology (medical), Pharmaceutical sciences, media_common, Pharmacology, business.industry, Management science, Drug discovery, Systems Biology, lcsh:RM1-950, medicine.disease, White Papers, Clinical trial, Substance abuse, lcsh:Therapeutics. Pharmacology, Drug development, Modeling and Simulation, Translational science, business, Systems pharmacology, Central Nervous System Agents
Abstract

The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross-disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior. The National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with the National Institute on Aging (NIA), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and National Center for Advancing Translational Sciences (NCATS), convened a workshop to explore and evaluate the potential of a quantitative systems pharmacology (QSP) approach to CNS drug discovery and development. The objective of the workshop was to identify the challenges and opportunities of QSP as an approach to accelerate drug discovery and development in the field of CNS disorders. In particular, the workshop examined the potential for computational neuroscience to perform QSP-based interrogation of the mechanism of action for CNS diseases, along with a more accurate and comprehensive method for evaluating drug effects and optimizing the design of clinical trials. Following up on an earlier white paper on the use of QSP in general disease mechanism of action and drug discovery, this report focuses on new applications, opportunities, and the accompanying limitations of QSP as an approach to drug development in the CNS therapeutic area based on the discussions in the workshop with various stakeholders.

Published
2020

11. Identification of concordant plasma lipid signatures in Alzheimer’s disease: Validation between two independent studies of Alzheimer’s disease

Author

Adam Alexander T. Smith, Kaushala S. Jayawardana, Matthias Arnold, Ashley I. Bush, Gavriel Olshansky, Xianlin Han, David Ames, Ian Martins, Agus Salim, Simon M. Laws, Kevin Huynh, Victor L. Villemagne, Corey Giles, Christopher C. Rowe, Kwangsik Nho, Rebecca Baillie, Andrew J. Saykin, Rima Kaddurah-Daouk, Brian G. Drew, Wei Ling Florence Lim, Pratishtha Chatterjee, Colin L. Masters, Ralph N. Martins, Natalie A. Mellett, and Peter J. Meikle

Subjects
Epidemiology, business.industry, Health Policy, Computational biology, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Lipidomics, Plasma lipids, Medicine, Identification (biology), Neurology (clinical), Geriatrics and Gerontology, business
Published
2020

12. Hallmarks of late‐onset Alzheimer’s disease in a humanized mouse model

Author

Gregory W. Carter, Rima Kaddurah-Daouk, Paul R. Territo, Bruce T. Lamb, Adrian L. Oblak, Christoph Preuss, Ravi S. Pandey, Harriet M. Williams, Stacey J. Sukoff Rizzo, Duc M. Duong, Matthias Arnold, Gareth R. Howell, Kevin P. Kotredes, Michael Sasner, and Nicholas T. Seyfried

Subjects
Epidemiology, business.industry, Health Policy, Late onset, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Humanized mouse, Immunology, Medicine, Model development, Neurology (clinical), Geriatrics and Gerontology, business, Analysis method
Published
2020

14. Clostridium shows a higher abundance in less neurovascular and neurodegenerative changes: A microbiome‐wide association study

Author

M. Arfan Ikram, Rima Kaddurah-Daouk, Shahzad Ahmad, Robert Kraaij, Hata Karamujić-Čomić, Cornelia M. van Duijn, Najaf Amin, Bruno Bonnechère, and Djawad Radjabzadeh

Subjects
Epidemiology, Health Policy, Systems biology, Biology, Neurovascular bundle, Omics, biology.organism_classification, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Clostridium, Developmental Neuroscience, Evolutionary biology, Abundance (ecology), Neurology (clinical), Microbiome, Geriatrics and Gerontology
Published
2020

15. Serum metabolome informs neuroimaging biomarkers for Alzheimer’s disease

Author

Alexandra Kueider-Paisley, Rebecca Baillie, Rima Kaddurah-Daouk, Andrew J. Saykin, Gregory Louie, Gabi Kastenmüller, Shannon L. Risacher, Xianlin Han, Colette Blach, Matthias Arnold, Siamak Mahmoudian Dehkordi, Kwangsik Nho, and P. Murali Doraiswamy

Subjects
Epidemiology, business.industry, Health Policy, Neuroimaging biomarkers, Disease, Bioinformatics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Metabolome, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020

16. Genome‐wide study of the human lipidome and links to Alzheimer’s disease risk

Author

Natalie A. Mellett, Matthias Arnold, Peter J. Meikle, Rebecca Baillie, Adam Alexander T. Smith, Eric Moses, Rima Kaddurah-Daouk, Corey Giles, Gavriel Olshansky, Andrew J. Saykin, David Ames, Victor L. Villemagne, Ian Martins, Ashley I. Bush, Kevin Huynh, Xianlin Han, Michael Inouye, Gemma Cadby, Gabi Kastenmüller, Anh Nguyen, Christopher C. Rowe, Kwangsik Nho, Simon M. Laws, Colin L. Masters, Ralph N. Martins, and Pratishtha Chatterjee

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Disease risk, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Lipidome, Biology, Genome
Published
2020

17. The role of the gut microbiome in cognitive function and Alzheimer’s disease

Author

Hata Karamujić-Čomić, Rima Kaddurah-Daouk, Shahzad Ahmad, M. Arfan Ikram, André G. Uitterlinden, Robert Kraaij, Thomas Hankemeier, Djawad Radjabzadeh, Bruno Bonnechère, Cornelia M. van Duijn, and Najaf Amin

Subjects
Epidemiology, business.industry, Health Policy, Cognition, Disease, Gut microbiome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Immunology, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020

18. A network‐based, multi‐omics atlas for target identification and prioritization in Alzheimer’s disease

Author

Maria A. Wörheide, Kwangsik Nho, Peter J. Meikle, Kevin Huynh, Matthias Arnold, Jan Krumsiek, Gabi Kastenmüller, Andrew J. Saykin, and Rima Kaddurah-Daouk

Subjects
Prioritization, Epidemiology, Computer science, Health Policy, Computational biology, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, Atlas (anatomy), medicine, Multi omics, Neurology (clinical), Geriatrics and Gerontology
Published
2020

19. Integrative metabolomics‐genomics approach reveals that pathways related to the metabolism of acylcarnitines and amines are new potential targets of Alzheimer’s disease

Author

Gabi Kastenmüller, Rebecca Baillie, Minghui Wang, Bin Zhang, Xianlin Han, Jan Krumsiek, Matthias Arnold, Kwangsik Nho, Andrew J. Saykin, Rima Kaddurah-Daouk, Beatriz Galindo-Prieto, and Emrin Horgusluoglu-Moloch

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Metabolomics, Developmental Neuroscience, Epidemiology, Health Policy, Genomics, Neurology (clinical), Disease, Computational biology, Metabolism, Geriatrics and Gerontology, Biology
Published
2020

21. F3‐02‐02: CIRCULATING METABOLITES’ ASSOCIATION WITH ALZHEIMER'S DISEASE–ASSOCIATED GENETIC VARIANTS

Author

Cornelia M. van Duijn, Matthias Arnold, Najaf Amin, Jun Liu, Rima Kaddurah-Daouk, Thomas Hankemeier, Siamak Mahmoudiandehkordi, M. Arfan Ikram, Hata Karamujić-Čomić, Kwangsik Nho, and Shahzad Ahmad

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Association (object-oriented programming), Genetic variants, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published
2018

22. F3‐02‐04: SERUM INDICES OF ETHANOLAMINE PLASMALOGENS AND PHOSPHATIDE METABOLISM IN THE COMBINED ADNI‐1/GO/2 COHORT: DOES THE LIVER CONTRIBUTE TO AD RISK BY FAILING TO SUPPLY KEY LIPIDS TO THE BRAIN?

Author

Rebecca Baillie, Rima Kaddurah-Daouk, Mitchel A. Kling, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Xianlin Han, Dayan B. Goodenowe, and Vijitha Senanayake

Subjects
0301 basic medicine, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Metabolism, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, Endocrinology, Developmental Neuroscience, Internal medicine, Cohort, medicine, Neurology (clinical), Ethanolamine plasmalogen, Geriatrics and Gerontology, business
Published
2018

23. P2‐253: EP300 IS ASSOCIATED WITH ALTERED BILE ACIDS IN ALZHEIMER'S DISEASE

Author

Kwangsik Nho, Matthias Arnold, Jingwen Yan, Shannon L. Risacher, Sairam Prabhakar Andhey, Siamak Mahmoudian Dehkordi, Andrew J. Saykin, and Rima Kaddurah-Daouk

Subjects
medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Endocrinology, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, EP300, business
Published
2018

24. P2‐261: APOLIPOPROTEIN J/CLUSTERIN IS THE PRIMARY DETERMINANT OF THE CHOLESTEROL EFFLUX CAPACITY OF CEREBROSPINAL FLUID

Author

Rima Kaddurah-Daouk, Nicholas N. Lyssenko, Antonino Picataggi, Leslie M. Shaw, Daniel J. Rader, Hannah J Szapary, Eleonora Cipollari, Jeffrey T. Billheimer, and Mitchel A. Kling

Subjects
medicine.medical_specialty, Clusterin, biology, Epidemiology, Chemistry, Cholesterol, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Cerebrospinal fluid, Endocrinology, Developmental Neuroscience, Internal medicine, medicine, biology.protein, Neurology (clinical), Efflux, Geriatrics and Gerontology, Apolipoprotein J
Published
2018

25. P4‐099: MULTIVARIATE CLUSTER PROFILING OF AMYLOID BETA, TAU, NEURODEGENERATION AND VASCULAR (ATNV) BIOMARKERS IN THE ADNI COHORT: IMPLICATIONS FOR COGNITION, –OMICS AND CLINICAL TRIALS

Author

Rima Kaddurah-Daouk, Liana G. Apostolova, Sujuan Gao, Andrew J. Saykin, Shannon L. Risacher, Jingwen Yan, and Kwangsik Nho

Subjects
Multivariate statistics, biology, Epidemiology, Amyloid beta, business.industry, Health Policy, Neurodegeneration, Cognition, Computational biology, Omics, medicine.disease, Clinical trial, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Cohort, biology.protein, medicine, Profiling (information science), Neurology (clinical), Geriatrics and Gerontology, business
Published
2018

26. P3‐069: CHOLESTEROL EFFLUX CAPACITY (CEC) IN PLASMA AND CEREBROSPINAL FLUID (CSF) OF PATIENTS WITH ALZHEIMER'S DISEASE (AD) AND MILD COGNITIVE IMPAIRMENT (MCI) AND COMPARISON SUBJECTS: EFFECTS OF GENDER AND DIAGNOSIS

Author

Daniel J. Rader, Leslie M. Shaw, Nicholas N. Lyssenko, Mitchel A. Kling, Jeffrey T. Billheimer, and Rima Kaddurah-Daouk

Subjects
0301 basic medicine, medicine.medical_specialty, Epidemiology, Disease, Gastroenterology, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, Developmental Neuroscience, Internal medicine, medicine, Mild cognitive impairment (MCI), business.industry, Cholesterol, Health Policy, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, chemistry, Neurology (clinical), Efflux, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Published
2018

27. F3‐02‐01: ALTERED BILE ACID METABOLITES IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE: RELATION TO NEUROIMAGING AND CSF BIOMARKERS

Author

Mitchel A. Kling, Rima Kaddurah-Daouk, Rebecca Baillie, Matthias Arnold, Colette Blach, Leslie M. Shaw, Alexandra Kueider-Paisley, Kwangsik Nho, Michael W. Weiner, P. Murali Doraiswamy, Siamak Mahmoudiandehkordi, Gabi Kastenmüller, Andrew J. Saykin, Xianlin Han, Gregory Louie, John Q. Trojanowski, and Shannon L. Risacher

Subjects
Bile acid, Epidemiology, medicine.drug_class, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Csf biomarkers, Immunology, medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive impairment, business
Published
2018

28. P1‐153: DIACYLGLYCEROL PATHWAY‐RELATED GENE PNPLA2 IS ASSOCIATED WITH CSF BIOMARKERS IN ALZHEIMER'S DISEASE

Author

Rima Kaddurah-Daouk, Kwangsik Nho, Shannon L. Risacher, Andrew J. Saykin, and Megan M. Bernath

Subjects
Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Csf biomarkers, Cancer research, Medicine, Neurology (clinical), Geriatrics and Gerontology, Related gene, business, Diacylglycerol kinase
Published
2018

29. P1-386: ASSOCIATION OF SERUM-BASED PLASMALOGENS WITH NEUROIMAGING AND GENETIC VARIATION IN ALZHEIMER'S DISEASE

Author

Vijitha Senanayake, P. Murali Doraiswamy, Gregory Louie, Matthias Arnold, Siamak MahmoudianDehkordi, Rima Kaddurah-Daouk, Xianlin Han, Gabi Kastenmüller, Dayan B. Goodenowe, Mitchel A. Kling, Rebecca Baillie, Andrew J. Saykin, Kwangsik Nho, Alexandra Kueider-Paisley, and Shannon L. Risacher

Subjects
Epidemiology, business.industry, Health Policy, Disease, Bioinformatics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Genetic variation, Medicine, Neurology (clinical), Geriatrics and Gerontology, Association (psychology), business
Published
2019

30. P2-153: METABOLOMICS-GENOMICS INTEGRATIVE APPROACH REVEALED NEW CANDIDATE GENES RELATED TO ALZHEIMER'S DISEASE

Author

Rima Kaddurah-Daouk, Andrew J. Saykin, Matthias Arnold, Emrin Horgusluoglu-Moloch, Bin Zhang, and Kwangsik Nho

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Candidate gene, Metabolomics, Developmental Neuroscience, Epidemiology, Health Policy, Genomics, Neurology (clinical), Disease, Computational biology, Geriatrics and Gerontology, Biology
Published
2019

31. P4-116: SERUM TRIGLYCERIDES IN ALZHEIMER'S DISEASE: RELATION TO NEUROIMAGING, CSF, AND GENETIC VARIATION

Author

John Q. Trojanowski, Rebecca Baillie, Oliver Fiehn, Leslie M. Shaw, Dinesh Kumar Barupal, Rima Kaddurah-Daouk, Sudeepa Bhattacharyya, Tanner Y. Jacobson, Alzheimer’s Disease Neuroimaging Initiative, Andrew J. Saykin, P. Murali Doraiswamy, Shannon L. Risacher, Michael W. Weiner, Kwangsik Nho, Matthias Arnold, and Megan M. Bernath

Subjects
Epidemiology, business.industry, Health Policy, Physiology, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Genetic variation, Medicine, Neurology (clinical), Geriatrics and Gerontology, Serum triglycerides, business
Published
2019

32. Metabolomic Signatures for Drug Response Phenotypes: Pharmacometabolomics Enables Precision Medicine

Author

Richard M. Weinshilboum and Rima Kaddurah-Daouk

Subjects
Pharmacology, Clinical pharmacology, Drug discovery, Systems biology, Computational biology, Biology, Precision medicine, Bioinformatics, Biomarkers, Pharmacological, Article, law.invention, Phenotype, Metabolomics, Pharmacogenetics, law, Pharmacogenomics, Drug Discovery, Metabolome, Drug response, Humans, Pharmacology (medical), Precision Medicine, Biomarkers, Metabolic Networks and Pathways, Systems pharmacology
Abstract

The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and Systems Pharmacology (QSP). This new research direction might significantly advance the discovery, development, and clinical use of therapeutic drugs. Research communities from computational biology, systems biology, and biological engineering--working collaboratively with pharmacologists, geneticists, biochemists, and analytical chemists--are creating and modeling large data on drug effects that is transforming our understanding of how these drugs work at a network level. In this review, we highlight developments in a new and rapidly growing field--pharmacometabolomics--in which large biochemical data-capturing effects of genome, gut microbiome, and environment exposures is revealing information about metabotypes and treatment outcomes, and creating metabolic signatures as new potential biomarkers. Pharmacometabolomics informs and complements pharmacogenomics and together they provide building blocks for QSP.

Published
2015

34. [F1–02–04]: INTEGRATING MULTI‐MODALITY IMAGING AND MULTI‐LAYER ‐OMICS TO ADVANCE THE SYSTEMS BIOLOGY OF ALZHEIMER's DISEASE

Author

Kelly N.H. Nudelman, Liana G. Apostolova, Kwangsik Nho, Rima Kaddurah-Daouk, Li Shen, Andrew J. Saykin, Jingwen Yan, Shannon L. Risacher, and Sungeun Kim

Subjects
Epidemiology, business.industry, Health Policy, Systems biology, Disease, Omics, Multi modality, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, Multi layer
Published
2017

35. [F2–01–03]: GUT DERIVED BILE ACID METABOLITES CORRELATE WITH STRUCTURAL AND FUNCTIONAL NEUROIMAGING MEASURES IN ALZHEIMER's DISEASE

Author

Therese Koal, Rebecca Baillie, Jessica D. Tenenbaum, Sudeepa Bhattacharyya, Alison A. Motsinger-Reif, Andrew J. Saykin, M. Arthur Moseley, Siamak Mahmoudian Dehkordi, Rima Kaddurah-Daouk, J. Will Thompson, Kwangsik Nho, Murali Doraiswamy, and Lisa St John Williams

Subjects
Bile acid, Epidemiology, business.industry, medicine.drug_class, Health Policy, Disease, Bioinformatics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Functional neuroimaging, Immunology, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2017

36. F1‐02‐02: Genetic Influence on Levels of Targeted Metabolites Associated with Alzheimer’s Disease

Author

Ramon Casanova, Kwangsik Nho, Therese Koal, Siamak Mahmoudiandehkordi, Leslie M. Shaw, Madhav Thambisetty, Gabi Kastenmüller, Xianlin Han, Kristaps Klavins, Alison A. Motsinger-Reif, Hongjie Zhu, Sudhir Varma, M. Arthur Moseley, Alzheimer’s Disease Neuroimaging Initiative, Karsten Suhre, Jessie Tenenbaum, John Q. Trojanowski, J. Will Thompson, Jon B. Toledo, Shannon L. Risacher, Sungeun Kim, Lisa St John Williams, Li Shen, Andrew J. Saykin, Murali Doraiswamy, Michael W. Weiner, Rebecca Baillie, Guido Dallmann, Cristina Legido-Quigley, and Rima Kaddurah-Daouk

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Immunology, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, business
Published
2016

37. P3‐157: Indices of Plasmalogen Biosynthesis in ADNI‐1 Baseline Serum Samples: Association with Progression to Dementia in Subjects with Mild Cognitive Impairment

Author

Rima Kaddurah-Daouk, Xianlin Han, Rebecca Baillie, Dayan B. Goodenowe, Mitchel A. Kling, Jessica D. Tenenbaum, Vijitha Senanayake, Alison A. Motsinger-Reif, Joseph E. Lucas, and Jon B. Toledo

Subjects
0301 basic medicine, medicine.medical_specialty, Plasmalogen, Epidemiology, business.industry, Health Policy, medicine.disease, Serum samples, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, Endocrinology, Developmental Neuroscience, Internal medicine, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business, Cognitive impairment, Association (psychology)
Published
2016

38. F1‐02‐01: The Alzheimer’s Metabolome: Relationship to Pathological Markers and Cognitive Decline in the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Author

Lisa St John Williams, Rima Kaddurah-Daouk, Madhav Thambisetty, P. Murali Doraiswamy, Therese Koal, J. Will Thompson, Jessie Tenenbaum, Leslie M. Shaw, M. Arthur Moseley, Sudhir Varma, Andrew J. Saykin, John Q. Trojanowski, Hongjie Zhu, Xianlin Han, Alison A. Motsinger-Reif, Siamak Mahmoudiandehkordi, Ramon Casanova, Karsten Suhre, Kristaps Klavins, Michael W. Weiner, Gabi Kastenmüller, Rebecca Baillie, Guido Dallmann, Cristina Legido-Quigley, Jon B. Toledo, and Sungeun Kim

Subjects
Epidemiology, business.industry, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Metabolome, Medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, business, Pathological, Neuroscience, Alzheimer's Disease Neuroimaging Initiative
Published
2016

39. O4‐12‐06: The Alzheimer's metabolome: Identification of novel markers and treatment targets

Author

Li Shen, P. Murali Doraiswamy, Andrew J. Saykin, Leslie M. Shaw, Rima Kaddurah-Daouk, Mitch A. Kling, Steven E. Arnold, Vijitha Senanayake, Dayan Goodenowe, Xianlin Han, Jon B. Toledo, Sungeun Kim, Tara Smith, and John Q. Trojanowski

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Treatment targets, Developmental Neuroscience, Epidemiology, Health Policy, Metabolome, Identification (biology), Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published
2015

40. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation

Author

Bruce G. Jenkins, Alpaslan Dedeoglu, Rima Kaddurah-Daouk, Ole A. Andreassen, M. Flint Beal, Mikhail B. Bogdanov, and Kimberly L. Ferrante

Subjects
Genetically modified mouse, Microdialysis, medicine.medical_specialty, biology, Glutamate receptor, medicine.disease_cause, Creatine, medicine.disease, Biochemistry, Superoxide dismutase, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Endocrinology, chemistry, In vivo, Internal medicine, biology.protein, medicine, Amyotrophic lateral sclerosis, Neuroscience, Oxidative stress
Abstract

Several lines of evidence implicate excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS). Transgenic mice with a superoxide dismutase mutation (G93A) have been utilized as an animal model of familial ALS (FALS). We examined the cortical concentrations of glutamate using in vivo microdialysis and in vivo nuclear magnetic resonance (NMR) spectroscopy, and the effect of long-term creatine supplementation. NMDA-stimulated and Ltrans-pyrrolidine-2,4-dicarboxylate (LTPD)-induced increases in glutamate were significantly higher in G93A mice compared with littermate wild-type mice at 115 days of age. At this age, the tissue concentrations of glutamate were also significantly increased as measured with NMR spectroscopy. Creatine significantly increased longevity and motor performance of the G93A mice, and significantly attenuated the increases in glutamate measured with spectroscopy at 75 days of age, but had no effect at 115 days of age. These results are consistent with impaired glutamate transport in G93A transgenic mice. The beneficial effect of creatine may be partially mediated by improved function of the glutamate transporter, which has a high demand for energy and is susceptible to oxidative stress.

Published
2001

41. Amyotrophic lateral sclerosis: Transgenic model and novel neuroprotective agent

Author

M. Flint Beal, Rima Kaddurah-Daouk, and Russell T. Matthews

Subjects
Mutation, Pathology, medicine.medical_specialty, General Neuroscience, SOD1, Substantia nigra, Biology, Mitochondrion, Creatine, medicine.disease_cause, medicine.disease, Neuroprotection, Cell biology, chemistry.chemical_compound, chemistry, medicine, Amyotrophic lateral sclerosis, Oxidative stress
Abstract

The discovery of mutations in the human SOD1 gene encoding (Cu, Zn SOD) in patients with familial amyotrophic lateral sclerosis (ALS) has made possible the development of etiological models of the disease. Expression of mutant SOD1 genes in transgenic mice (FALS mice) causes progressive paralytic disease whose general features resemble ALS in humans. Extensive studies strongly suggest that Cu, Zn SOD mutations cause an adverse gain of function that results in enhanced generation of damaging oxygen radicals. Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features in the FALS mice harboring the SOD mutations. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. Creatine buffers against ATP depletion and inhibits the opening of the mitochondrial transition pore, a complex of proteins implicated in apoptosis. We found that oral administration of creatine to FALS mice expressing the G93A mutation produced a dose-dependent improvement in motor performance, extended survival and protected against loss of motor neurons and substantia nigra neurons. Additionally creatine protected against increases in biochemical indices of oxidative damage. The development of the FALS mice enables drug discovery studies in ALS.

Published
2000

42. O4–01–06: Targeted lipidomic pathway‐guided genetic association with Alzheimer's disease–relevant endophenotypes

Author

Rima Kaddurah-Daouk, Mitchel A. Kling, Kwangsik Nho, Vijay K. Ramanan, P. Murali Doraiswamy, John Q. Trojanowski, Xianlin Han, Patrick Sullivan, Shannon L. Risacher, Sungeun Kim, Hongjie Zhu, Li Shen, Andrew J. Saykin, and Steven E. Arnold

Subjects
Epidemiology, business.industry, Health Policy, Computational biology, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Endophenotype, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Genetic association
Published
2013

43. P3–056: Alterations in metabolic pathways and networks in mild cognitive impairment and early Alzheimer's disease

Author

Xianlin Han, Sungeun Kim, Swati Sharma, P. Murali Doraiswamy, Li Shen, John Q. Trojanowski, Andrew J. Saykin, Mitchel A. Kling, Wayne R. Matson, Kwangsik Nho, Rima Kaddurah-Daouk, Steven E. Arnold, and Hongjie Zhu

Subjects
Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Metabolic pathway, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Cognitive impairment, Neuroscience
Published
2013

45. Pharmacometabolomics Reveals That Serotonin Is Implicated in Aspirin Response Variability

Author

Cynthia M. Kuhn, Rima Kaddurah-Daouk, Hongjie Zhu, R. Ramaker, Thomas L. Ortel, Rob J. Vreeken, Adrie Dane, Thomas Hankemeier, Anastasia Georgiades, Christina G. Perry, Joshua P. Lewis, Amber L. Beitelshees, Amy C. Harms, Richard B. Horenstein, Sandrine Ellero-Simatos, Laura M. Yerges-Armstrong, C. L. Sánchez, Alan R. Shuldiner, Hankemeier, Thomas, Kaddurah-Daouk, R, Leiden University, University of Maryland School of Medecine, Partenaires INRAE, Duke University Medical Center, RWTH Aachen University, Department of Psychiatry and Behavioral Sciences, and Duke University [Durham]

Subjects
0303 health sciences, Aspirin, business.industry, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Pharmacology, Response Variability, 3. Good health, Platelet reactivity, 03 medical and health sciences, 0302 clinical medicine, Modeling and Simulation, Cohort, Medicine, Original Article, Pharmacology (medical), Platelet, Serotonin, business, Incubation, Ex vivo, 030304 developmental biology, medicine.drug
Abstract

International audience; While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10−4, N = 12). These results suggest that serotonin is implicated in aspirin response variability.

Published
2014

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