Longitudinal metabolomic profiling of biogenic amines in plasma and CSF, and their correlation, reveals sex-specific and age changes in TgF344 Alzheimer’s disease transgenic and wildtype rats

BACKGROUND: Alterations in amine metabolism have been implicated in Alzheimer's disease (AD), but the relationships between plasma and cerebrospinal fluid (CSF) amine levels remain insufficiently understood. AIM: To investigate longitudinal changes in amines in plasma and CSF, as well as their cross-matrix correlations, in male and female TgF344-AD transgenic rats compared with wild-type (WT) controls. METHOD: LC-MS-based targeted metabolomics was used to quantify 60 plasma amines and 55 CSF amines in male and female TgF344-AD and WT rats at 12, 25, 50 and 85 weeks of age. Generalized linear models, Pearson correlations, and Fisher's r-to-z transformation were applied for statistical analysis. RESULTS: In plasma, age- and sex-associated differences were observed. At 25 weeks, three amines (4-hydroxy-proline, homocitrulline, and hydroxylysine) showed significantly increased levels in male TgF344-AD rats after multiple-testing correction. Additional trend-level changes were observed at 12, 50, and 85 weeks. In CSF, no amines passed the significance threshold after multiple-testing correction, although descriptive age- and sex-associated patterns were observed, with earlier changes in males and later-stage trends in females. CSF-plasma correlations tended to be stronger in TgF344-AD rats than in WT rats, with relatively strong correlations for alpha-aminobutyric acid, citrulline, N6,N6,N6-trimethyl-lysine, and putrescine. CONCLUSIONS: Body fluid, age- and sex-dependent amine alterations in CSF and plasma of TgF344-AD rats compared to WT controls provide important insights into AD disease processes and may aid early diagnosis and therapeutic targeting.