TY - JOUR
T1 - Circulating ethanolamine plasmalogen indices in Alzheimer's disease
T2 - Relation to diagnosis, cognition, and CSF tau
AU - for the Alzheimer's Disease Metabolomics Consortium (ADMC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI)
AU - Kling, Mitchel A.
AU - Goodenowe, Dayan B.
AU - Senanayake, Vijitha
AU - MahmoudianDehkordi, Siamak
AU - Arnold, Matthias
AU - Massaro, Tyler J.
AU - Baillie, Rebecca
AU - Han, Xianlin
AU - Leung, Yuk Yee
AU - Saykin, Andrew J.
AU - Nho, Kwangsik
AU - Kueider-Paisley, Alexandra
AU - Tenenbaum, Jessica D.
AU - Wang, Li San
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Kaddurah-Daouk, Rima F.
N1 - Funding Information:
Dayan B. Goodenowe is the CEO and President of Prodrome Sciences Inc., and was the former CEO and President of Phenomenome Discoveries Inc. Vijitha Senanayake is an employee of Prodrome Sciences Inc. and was previously an employee of Phenomenome Discoveries, Inc. Rebecca Baillie is employed as Chief of Staff at Rosa & Co. Leslie M. Shaw received research support from NIH/NIA, ADNI (AG024904), and UPenn ADCC Biomarker Core (AG010124), MJFox Foundation for PD research, Roche, Lilly; provides QC oversight for Roche Elecsys CSF AD biomarker immunoassays for ADNI; and is a consultant for Roche, Lilly, and Novartis. Andrew J. Saykin has been supported by multiple grants from the NIA, NCI, and NCAA/DoD as well as collaborative research support from Eli Lilly unrelated to the work reported here. He also received nonfinancial support from Avid Radiopharmaceuticals and Neurovision, and has served as a consultant to Arkley BioTek and Bayer. He received support from Springer‐Nature as Editor in Chief of , outside the scope of the work submitted here. John Q. Trojanowski may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a co‐inventor and he received revenue from the sale of Avid to Eli Lily as a co‐inventor on imaging‐related patents submitted by the University of Pennsylvania. Rima F. Kaddurah‐Daouk is inventor on key patents in the field of metabolomics including applications for Alzheimer's disease. All other authors report no disclosures. Brain Imaging and Behavior
Funding Information:
Funding for ADMC (Alzheimer's Disease Metabolomics Consortium, led by Dr R.K.‐D. at Duke University) was provided by the National Institute on Aging grant R01AG046171, a component of the Accelerated Medicines Partnership for AD (AMP‐AD) Target Discovery and Preclinical Validation Project ( https://www.nia.nih.gov/research/dn/amp-ad-target-discovery-and-preclinical-validation-project ) and the National Institute on Aging grant RF1 AG0151550, a component of the MOVE‐AD Consortium (Molecular Mechanisms of the Vascular Etiology of AD Consortium https://www.nia.nih.gov/news/decoding-molecular-ties-between-vascular-disease-and-alzheimers ). 2
Funding Information:
The work of various Consortium Investigators are also supported by various NIA grants (U01AG024904‐09S4, P50NS053488, R01AG19771, P30AG10133, P30AG10124, K01AG049050), the National Library of Medicine (R01LM011360, R00LM011384), and the National Institute of Biomedical Imaging and Bioengineering (R01EB022574). Additional support came from Helmholtz Zentrum, the Alzheimer's Association, the Indiana Clinical and Translational Science Institute, and the Indiana University‐IU Health Strategic Neuroscience Research Initiative.
Funding Information:
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Publisher Copyright:
© 2020 the Alzheimer's Association
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability. Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cerebrospinal fluid (CSF) AD biomarkers. Results: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 × 10−5) and PBV (P = 1.99 × 10−4), and AD versus LMCI with PL/PE (P = 1.85 × 10−4). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 × 10−6; PBV: P = 6.92 × 10−5) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 × 10−9; PBV: P = 6.50 × 10−9). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADNI, CSF total-tau was negatively associated with PL-PX (P = 5.55 × 10−6) and PBV (P = 7.77 × 10−6). Additionally, CSF t-tau/Aβ1-42 ratio was negatively associated with these same indices (PL-PX, P = 2.73 × 10−6; PBV, P = 4.39 × 10−6). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/Aβ1-42 (P = 0.021). CSF Aβ1-42 was not significantly associated with any of these indices in either cohort. Discussion: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens.
AB - Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability. Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cerebrospinal fluid (CSF) AD biomarkers. Results: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 × 10−5) and PBV (P = 1.99 × 10−4), and AD versus LMCI with PL/PE (P = 1.85 × 10−4). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 × 10−6; PBV: P = 6.92 × 10−5) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 × 10−9; PBV: P = 6.50 × 10−9). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADNI, CSF total-tau was negatively associated with PL-PX (P = 5.55 × 10−6) and PBV (P = 7.77 × 10−6). Additionally, CSF t-tau/Aβ1-42 ratio was negatively associated with these same indices (PL-PX, P = 2.73 × 10−6; PBV, P = 4.39 × 10−6). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/Aβ1-42 (P = 0.021). CSF Aβ1-42 was not significantly associated with any of these indices in either cohort. Discussion: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens.
KW - case-control study
KW - dementia
KW - lipidomics
KW - mass spectrometry
KW - metabolomics
KW - mild cognitive impairment
KW - phosphatidylethanolamines
KW - plasmenylethanolamines
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U2 - 10.1002/alz.12110
DO - 10.1002/alz.12110
M3 - Article
AN - SCOPUS:85088456178
VL - 16
SP - 1234
EP - 1247
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 9
ER -