Untargeted and Targeted Cerebrospinal Fluid Neurometabolomics via Chromatography–Mass Spectrometry-Based Methods

Neuroscience is a rapidly advancing field; however, a comprehensive understanding of brain function at the molecular, cellular, and systems levels remains incomplete. Neurological and psychiatric disorders represent a major global health burden, highlighting the need for improved diagnostic and therapeutic strategies. Cerebrospinal fluid (CSF) is one of the most informative biofluids for investigating central nervous system (CNS) pathology due to its close biochemical relationship with brain tissue. Recent advances in neurometabolomics, defined as the comprehensive analysis of small-molecule metabolites in CSF, have been driven by the development of highly sensitive and informative mass spectrometry-based techniques. These approaches enable the identification of disease-associated metabolic signatures. This review summarizes current chromatography–mass spectrometry-based methods used in both untargeted and targeted CSF metabolomics, with particular emphasis on their analytical performance, reproducibility, and limitations. Special attention is given to method standardization and validation, as well as to the identification of reliable metabolic biomarkers for the diagnosis and monitoring of neurological disorders, including neurodegenerative, psychiatric, oncological, and neuroinflammatory diseases.