Deep Brain Stimulation rescues the homeostasis disruption of circulating D- and L-amino acids level in men with Parkinson’s Disease

Abstract Recent evidence indicates a marked downregulation of circulating D- and L-amino acids involved in regulating glutamatergic NMDAR function in Parkinson’s disease (PD) patients compared with matched controls. However, the extent to which disease progression and antiparkinsonian therapies contribute to this dysregulation remains unclear. To address these issues, in the present study we measured by High Performance Liquid Chromatography the concentrations of glutamatergic system-related D- and L-amino acids and their precursors in the plasma of male and female healthy controls (HC) and PD patients across three distinct clinical stages and treatment conditions: (1) early stage L-DOPA naïve patients treated with MAO-B inhibitors; (2) mid-stage patients treated with L-DOPA; and (3) advanced stage patients receiving Deep Brain Stimulation in the subthalamic nucleus (STN-DBS) plus L-DOPA. Our results reveal notable reduction of circulating neuroactive D- and L-amino acids exclusively in male PD patients, while female patients exhibit a similar directional trend. In male patients, this dysregulation manifests early, with L-DOPA–naïve individuals showing decreased plasma levels of L-glutamate and L-aspartate. In mid-stage L-DOPA-treated PD patients, amino acid reductions extend to L-alanine, L-serine, L-glutamine, L-asparagine, and L–threonine. Remarkably, in advanced PD patients, with a median disease duration of ∼ 23 years, STN–DBS normalizes the blood concentrations of these amino acids to those observed in HC. In conclusion, our study highlights the potential of circulating D- and L-amino acid dysregulation as an early biomarker of PD and demonstrates that, in contrast to L-DOPA therapy, the STN-DBS confers systemic metabolic benefits even at advanced stages of the disease. Competing Interest Statement The authors have declared no competing interest. Footnotes This version of the manuscript has been revised to improve the writing style and correct typos