Challenges in LC–MS-based metabolomics for Alzheimer’s disease early detection: targeted approaches versus untargeted approaches

Abstract

Background Alzheimer's disease (AD) is one of the most common causes of dementia in old people. Neuronal deficits such as loss of memory, language and problem-solving are severely compromised in affected patients. The molecular features of AD are Aβ deposits in plaques or in oligomeric structures and neurofibrillary tau tangles in brain. However, the challenge is that Aβ is only one piece of the puzzle, and recent findings continue to support the hypothesis that their presence is not sufficient to predict decline along the AD outcome. In this regard, metabolomic-based techniques are acquiring a growing interest for either the early diagnosis of diseases or the therapy monitoring. Mass spectrometry is one the most common analytical platforms used for detection, quantification, and characterization of metabolic biomarkers. In the past years, both targeted and untargeted strategies have been applied to identify possible interesting compounds. Aim of review The overall goal of this review is to guide the reader through the most recent studies in which LC–MS-based metabolomics has been proposed as a powerful tool for the identification of new diagnostic biomarkers in AD. To this aim, herein studies spanning the period 2009–2020 have been reported. Advantages and disadvantages of targeted vs untargeted metabolomic approaches have been outlined and critically discussed.

Multiplatform untargeted metabolomics

“…Despite these advantages, a single analytical platform approach still dominates the metabolomics field, which may be a contributing factor to an abundance of tenuous metabolomics research studies populating the scientific literature. It may also explain the low reproducibility seen across multiple clinical studies aimed at identifying disease biomarkers 42,54b . MS methods have faced a growing concern over reproducibility and the accuracy of metabolite identifications 47k .…”

“…We recently explored the reproducibility of metabolomics platforms by conducting a meta‐analysis of 24 pancreatic ductal adenocarcinoma (PDAC) metabolomics studies from the scientific literature 54b . The majority of these studies relied on a single analytical platform, either NMR or LC–MS, to identify potential biomarkers for PDAC.…”

“…While the concept of metabolome coverage deals with the absolute number of discoverable metabolites, the confidence or reliability in a metabolite identification is not as simple to define. The low reproducibility in metabolite assignments between replicate metabolomics studies is a growing concern 54 . This reliability is related to both the uncertainty in peak detection and the number of redundant and unique spectral features attributed to a metabolite 55 .…”

Therapeutic effect and mechanism of Anemarrhenae Rhizoma on Alzheimer’s disease based on multi-platform metabolomics analyses

“…With the continuous improvements in the related technologies, LC- Frontiers in Pharmacology frontiersin.org Frontiers in Pharmacology frontiersin.org QTOF/MS has unequivocally become an established informative technique for metabolomics studies and has been utilized mostly (Khamis et al, 2017;Chaleckis et al, 2019). Previous studies have concluded that a vast number of metabolites studied using the LC-QTOF/MS platform could help shed light on alteration in the metabolic pathway in AD (Reveglia et al, 2021). Yet it is worth noting that, in this research, a total of 10 low molecular weight metabolites such as butanoic acid, citrulline, urea, cholesterol, and lactic acid were detected, and nine of which had not been identified by the LC-QTOF/MS method.…”

High‐Fat Diet Alters Acylcarnitine Metabolism of the Retina and Retinal Pigment Epithelium/Choroidal Tissues in Laser‐Induced Choroidal Neovascularization Rat Models

“…The essential role of targeted metabolomics as a translational approach for clinical purposes has been demonstrated in biomarker studies of challenging diseases, including cardiovascular disease, [ 19 ] cancer, [ 20 ] and Alzheimer's disease, [ 21 ] as well as response to drug therapy in AMD. [ 22 ] However, the plasma sample is often influenced by external variables, such as diet and lifestyle, and may only partially reflect the metabolic status that occurs in the retina and RPE/choroid layers.…”