Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry

Abstract

Background During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in cerebrospinal fluid (CSF) has not been thoroughly explored. Methods In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC–MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20–87 years without obesity or diabetes were analyzed. Results We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood–brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison. Conclusions Our LC–MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration.

Critical Factors in Sample Collection and Preparation for Clinical Metabolomics of Underexplored Biological Specimens

“…Thus, the CSF is a key biological specimen for analyzing brain metabolism and understanding CNS diseases, providing insights into disease mechanisms [ 95 ]. Due to the increasing number of patients diagnosed with neurodegenerative and mental disorders such as multiple sclerosis [ 96 ], Parkinson’s disease [ 97 , 98 ], Alzheimer’s disease [ 99 ], epilepsy [ 100 ], and other slowly progressive diseases, the interest in the study of the CSF has expanded [ 93 , 101 , 102 , 103 ].…”

“…Unlike the other biological specimens discussed in this review, CSF sample collection is invasive, performed through lumbar puncture (LP), also known as a spinal tap. The patient is placed in the lateral recumbent position or remains sitting and leaning forward, and a sterile spinal needle is carefully inserted between vertebrae into the subarachnoid space at L3 /4 or L4/5 [ 103 ]. The volume of the CSF sampled is around 2.0–5.0 mL, and after centrifugation, the supernatant is stored at −80 °C [ 93 ].…”