Neurotransmitter imbalance, glutathione depletion and concomitant susceptibility increase in Parkinson’s disease

Abstract

Background

Emerging insights into the pathophysiology of Parkinson’s disease (PD) underscore the involvement of dysregulated neurotransmission, iron accumulation and oxidative stress. Nonetheless, the excitatory and inhibitory neurometabolites, the antioxidant glutathione (GSH), and magnetic susceptibility are seldom studied together in the clinical PD literature.

Methods

We acquired MEGA-PRESS and multi-echo gradient echo sequences from 60 PD patients and 47 healthy controls (HCs). Magnetic resonance spectroscopy voxels were respectively positioned in the midbrain to quantify neurotransmitter including γ-aminobutyric acid (GABA) and glutamate plus glutamine, and in the left striatum to estimate GSH levels. Group differences in metabolite levels normalized to total creatine (Cr) and their clinical relevance were determined. Furthermore, relationships among GSH levels, neurotransmitter estimates and susceptibility values were explored in both PD patients and HCs.

Results

PD patients exhibited reduced midbrain GABA levels (P = 0.034, P_FDR = 0.136), diminished GSH in the left striatum (P = 0.032, P_FDR = 0.096), and increased susceptibility values in the substantia nigra (P_FDR < 0.001). Mesencephalic choline levels were correlated with the severity of rapid eye movement sleep behavior disorders symptoms, whereas striatal N-acetylaspartate levels were linked to Hoehn-Yahr stage and motor symptom severity. Notably, the disruption of associations between striatal GSH levels and susceptibility values in globus pallidus, as well as midbrain GABA levels, were evident in PD.

Conclusions

These findings offer compelling evidence for metabolic dysregulation in PD, characterized by a concomitant reduction in GABA and GSH levels, alongside iron deposition.