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bioRxiv · 10.1101/2020.05.16.093559

Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: A pilot study

Natarajan, K.·Ullgren, A.·Khoshnood, B.·johansson, c.·Laffita, J.·Pannee, J.·Zetterberg, H.·Blennow, K.·Graff, C.
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Abstract

Background and ObjectivePSEN1-H163Y carriers, at the presymptomatic stage, have reduced 18FDG-PET binding in the cerebrum of the brain [1]. This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomatic PSEN1 mutation carriers was analyzed to understand associated metabolic changes. MethodsWe analyzed plasma from non-carriers (NC, n=8) and presymptomatic PSEN1-H163Y mutation carriers (MC, n=6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of A{beta}1-42/A{beta}1-40, using Spearmans correlation. Altered metabolites were subjected to Ingenuity Pathways Analysis (IPA). ResultsWhen comparing between presymptomatic MC and NC, the levels of 116 different metabolites were altered. Out of 116, only 23 were annotated metabolites, which include amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC, glucose and uric acid were correlated with the ratio of plasma A{beta}1-42/A{beta}1-40 (p < 0.05). ConclusionThis study finds dysregulated metabolite classes, which are changed before the disease onset. Also, it provides an opportunity to compare with sporadic Alzheimers Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimers Disease (FAD) cohort. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=31 SRC="FIGDIR/small/093559v1_ufig1.gif" ALT="Figure 1"> View larger version (9K): org.highwire.dtl.DTLVardef@1f5adccorg.highwire.dtl.DTLVardef@653757org.highwire.dtl.DTLVardef@1144ba0org.highwire.dtl.DTLVardef@171272a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Natarajan, K., Ullgren, A., Khoshnood, B., johansson, c., Laffita, J., Pannee, J., Zetterberg, H., Blennow, K., Graff, C.. 2020-05-17. Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: A pilot study. https://doi.org/10.1101/2020.05.16.093559

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