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

Abstract

Background and objective: PSEN1-H163Y carriers, at the presymptomatic stage, have reduced ¹⁸ FDG-PET binding in the cerebrum of the brain (Scholl et al., Neurobiol Aging 32:1388-1399, 2011). 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.

Methods: We analyzed plasma from noncarriers (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 Aβ_{1-42/A β 1-40} , using Spearman's correlation. Altered metabolites were subjected to Ingenuity Pathway Analysis (IPA).

Results: Based on principal component analysis the plasma metabolite profiles were divided into dataset A and dataset B. In dataset A, when comparing between presymptomatic MC and NC, the levels of 79 different metabolites were altered. Out of 79, only 14 were annotated metabolites. In dataset B, 37 metabolites were significantly altered between presymptomatic MC and NC and nine metabolites were annotated. In both datasets, annotated metabolites represent amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC was positively correlated, uric acid and glucose were negatively correlated with the ratio of plasma Aβ_1-42 /Aβ_1-40 (P < 0.05).

Interpretation: This study finds dysregulated metabolite classes, which are changed before the disease symptom onset. Also, it provides an opportunity to compare with sporadic Alzheimer's Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimer's Disease (FAD) cohort.

Figure 1

Heat map showing similarities between samples of the metabolites that were differentially expressed between NC (noncarrier group, dark blue) and the PSEN1‐H163Y MC (mutation carrier group, Green). Sample from the reduced penetrance mutation carrier (RP) case is represented by yellow color. Legend: Red (upregulated metabolite), Blue (downregulated metabolite) and white (no modulation). (A) Samples from dataset A. (B) Samples from dataset B.

Figure 2

(A) Enriched canonical pathways for 23 annotated metabolites, which were differentially expressed between presymptomatic PSEN1 MC and NC. (B–D) In “Molecular and Cellular Functions” terms, identified metabolites were associated with (B) “Production of reactive oxygen species” (C) “Peroxidation of lipid,” (D) “Neuronal cell death”. (E–F). In “Disease and Disorders” terms, under “Metabolic disease” (E) “Glucose metabolism disorder” and in “Inflammatory disease” (F) “Chronic inflammatory disorder” metabolite network was identified.

Figure 3

(A) Network of metabolites and its regulators involved in the “Cell cycle.” (B) Molecular network of differentially expressed metabolites and their upstream regulators involved in the “Lipid metabolism.”