Can Small Molecules Provide Clues on Disease Progression in Cerebrospinal Fluid from Mild Cognitive Impairment and Alzheimer’s Disease Patients?

13 December 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Alzheimer’s Disease (AD) is a complex and multifactorial neurodegenerative disease, which is currently diagnosed via clinical symptoms and non-specific biomarkers (such as Aβ1-42, t-Tau, and p-Tau) measured in cerebrospinal fluid (CSF), which alone do not provide sufficient insights into disease progression. In this pilot study, these biomarkers were complemented with small molecule analysis using non-target high resolution mass spectrometry (NT-HRMS) coupled to liquid chromatography (LC) on the CSF of three groups; AD, Mild Cognitive Impairment (MCI) due to AD, and a non-demented control group (ND). An open source cheminformatics pipeline based on MS-DIAL and patRoon was enhanced using CSF- and AD-specific suspect lists to assist in data interpretation. ChemRICH analysis revealed a significant increase of hydroxybutyrates in AD, including 3-hydroxy butanoic acid (BHBA), which was found at higher levels in AD compared to MCI and ND. Furthermore, a highly sensitive target LC-MS method was used to quantify 35 bile acids (BAs) in the CSF, revealing several statistically significant differences including higher dehydrolithocholic acid levels and decreased conjugated BAs levels in AD. This work provides several promising small molecule hypotheses that could be used to help track the progression of AD in CSF samples.

Keywords

high resolution mass spectrometry
liquid chromatography
exposomics
cheminformatics
cerebrospinal fluid
Alzheimer's disease
metabolomics
bile acids

Supplementary materials

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Supporting Information (document) for main manuscript
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A PDF word file contains figures and additional details regarding material and methods (S1), results and discussion (S2) plus Figures S1-S18. An Excel file contains supplementary tables Table S1-S15.
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Supporting Information (tables) for main manuscript
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This Excel file contains supplementary tables: Tables S1-S15 (table of contents within)
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