Ultra-performance liquid chromatography-mass spectrometry analysis of post-mortem brain tissue reveals specific amino acid profile dysregulation in Parkinson’s Disease and Alzheimer’s Disease patients

Background Combined metabolomic and HPLC-based analyses have identified significant metabolic alterations in serum and plasma amino acid levels of Parkinson’s disease (PD) patients, underscoring their potential as biomarkers. However, it remains unclear whether these biochemical changes also manifest within the central nervous system or are confined to peripheral metabolism, reflecting systemic metabolic disturbances. Methods To address this issue, here we measured the levels of 44 different amino acids in post-mortem brain samples from MPTP-intoxicated, L-DOPA-treated monkeys and PD patients at different Braak Lewy body (LB) stages, compared to their respective controls, through targeted Ultra-performance liquid chromatography–mass spectrometry (UPLC-MS). Results In MPTP-intoxicated monkeys, UPLC-MS revealed significant elevations in GABA, citrulline, threonine, isoleucine, phenylalanine, valine, glycine, and serine in the putamen, whereas we failed to detect alterations in the superior frontal gyrus (SFG). In PD patients, caudate-putamen (CPu) analysis demonstrated consistent serine upregulation across Braak LB stages 3–4 and 6, with stage 6 specifically showing additional proline increases and phosphoethanolamine decreases. Notably, serine was the sole amino acid significantly altered in both the putamen of MPTP-intoxicated monkeys and the CPu of PD patients. No significant amino acid alterations were observed in the SFG of PD patients, mirroring the findings in monkeys. In contrast, Alzheimer’s disease (AD) patient SFG samples showed significant increases in tryptophan, phenylalanine, threonine, tyrosine, and methionine relative to controls. Conclusions These findings demonstrate that cerebral amino acid alterations in PD are region-specific and primarily localized to brain areas receiving nigrostriatal dopaminergic innervation. Moreover, the cortical amino acid profile in AD differs substantially from that in PD, suggesting disease-specific metabolic signatures in distinct neurodegenerative conditions.