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Metabolic network failures in Alzheimer's disease-A biochemical road map.
Alzheimers Dement. 13, 965-984 (2017)
INTRODUCTION: The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. METHODS: Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. RESULTS: Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. DISCUSSION: Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
9.478
2.528
157
222
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Acylcarnitines ; Alzheimer's Disease ; Biochemical Networks ; Biomarkers ; Branched-chain Amino Acids ; Dementia ; Metabolism ; Metabolomics ; Metabonomics ; Pharmacometabolomics ; Pharmacometabonomics ; Phospholipids ; Precision Medicine ; Serum ; Sphingomyelins ; Systems Biology; Mild Cognitive Impairment; Pittsburgh Compound-b; Neurodegenerative Disorders; Mass-spectrometry; Older-adults; Mouse Model; Brain; Biomarker; Insulin; Plasmalogen
Sprache
Veröffentlichungsjahr
2017
HGF-Berichtsjahr
2017
ISSN (print) / ISBN
1552-5260
e-ISSN
1552-5279
Zeitschrift
Alzheimer's & Dementia
Quellenangaben
Band: 13,
Heft: 9,
Seiten: 965-984
Verlag
Elsevier
Verlagsort
New York, NY [u.a.]
Begutachtungsstatus
Peer reviewed
POF Topic(s)
30505 - New Technologies for Biomedical Discoveries
Forschungsfeld(er)
Enabling and Novel Technologies
PSP-Element(e)
G-503700-001
WOS ID
WOS:000408861400002
Scopus ID
85015733333
PubMed ID
28341160
Erfassungsdatum
2017-06-19