Metabolic profiling of neocortical tissue discriminates Alzheimer’s disease from mild cognitive impairment, high pathology controls, and normal controls

Abstract

Background Alzheimer’s disease (AD) is the most common cause of dementia, accounting for an estimated 60 to 80% of cases, and is the sixth-leading cause of death in the United States. While considerable advancements have been made in the clinical care of AD, it remains a complicated disorder that can be difficult to identify definitively in its earliest stages. Recently, mass spectrometry (MS)-based metabolomics has shown significant potential for elucidation of disease mechanisms and identification of therapeutic targets as well diagnostic and prognostic markers that may be useful in resolving some of the difficulties affecting clinical AD studies, such as effective stratification. Methods In this study, complementary gas chromatography- and liquid chromatography-MS platforms were used to detect and monitor 2,080 metabolites and features in 48 post-mortem tissue samples harvested from the superior frontal gyrus of male and female subjects. Samples were taken from four groups: 12 normal control (NC) patients, 12 cognitively normal subjects characterized as high pathology controls (HPC), 12 subjects with non-specific mild cognitive impairment (MCI), and 12 subjects with AD. Results Multivariate statistics informed the construction and cross-validation (p < 0.01) of partial least squares-discriminant analysis (PLS-DA) models defined by a 9-metabolite panel of disease markers (lauric acid, stearic acid, myristic acid, palmitic acid, palmitoleic acid, and four unidentified mass spectral features). Receiver operating characteristic analysis showed high predictive accuracy of the resulting PLS-DA models for discrimination of NC (97%), HPC (92%), MCI (~ 96%), and AD (~ 96%) groups. Pathway analysis revealed significant disturbances in lysine degradation, fatty acid metabolism, and the degradation of branched-chain amino acids. Network analysis showed significant enrichment of 11 enzymes, predominantly within the mitochondria. Conclusions The results expand basic knowledge of the metabolome related to AD and reveal pathways that can be targeted therapeutically. This study also provides a promising basis for the development of larger multi-site projects to validate these candidate markers in readily available biospecimens such as blood to enable the effective screening, rapid diagnosis, accurate surveillance, and therapeutic monitoring of AD.

Microbiome and metabolome profiles of high screen time in a cohort of healthy college students

“…The targeted LC-MS/MS method used here was modeled after that developed and used in a growing number of studies [71][72][73] . Briefly, all LC-MS/MS experiments were performed on an Agilent 1290 UPLC-6490 QQQ-MS system.…”

Metabolites Associated With Fatigue and Physical Activity in Childhood Cancer

“…The targeted LC-MS/MS method in this study was modeled after that developed and used in a growing number of studies extracting a detailed list of confirmed metabolites (Jasbi et al, 2021; Shi et al, 2019; Zhu et al, 2015). Briefly, we included ∼300 metabolites (additional information available from the authors by request) selected from >35 metabolic pathways of biological significance to energy expenditure (such as glycolysis, TCA cycle, purine metabolism, and amino acid metabolism).…”

Ischemic stroke and dietary vitamin B12 deficiency in old-aged females impaired motor function, increased ischemic damage size, and changed metabolite profiles in brain and cecum tissue

“…The targeted LC-MS/MS method used here was modeled after that developed and used in a growing number of studies (Bapat et al 2021;Jasbi, Baker, et al 2019;Jasbi et al 2021;Jasbi, Mitchell, et al 2019;Wang et al 2019). Briefly, all LC-MS/MS experiments were performed on an Agilent 1290 UPLC-6490 QQQ-MS system.…”