Promising Metabolite Profiles in the Plasma and CSF of Early Clinical Parkinson's Disease

Abstract

Parkinson's disease (PD) shows high heterogeneity with regard to the underlying molecular pathogenesis involving multiple pathways and mechanisms. Diagnosis is still challenging and rests entirely on clinical features. Thus, there is an urgent need for robust diagnostic biofluid markers. Untargeted metabolomics allows establishing low-molecular compound biomarkers in a wide range of complex diseases by the measurement of various molecular classes in biofluids such as blood plasma, serum, and cerebrospinal fluid (CSF). Here, we applied untargeted high-resolution mass spectrometry to determine plasma and CSF metabolite profiles. We semiquantitatively determined small-molecule levels (≤1.5 kDa) in the plasma and CSF from early PD patients (disease duration 0–4 years; n = 80 and 40, respectively), and sex- and age-matched controls (n = 76 and 38, respectively). We performed statistical analyses utilizing partial least square and random forest analysis with a 70/30 training and testing split approach, leading to the identification of 20 promising plasma and 14 CSF metabolites. These metabolites differentiated the test set with an AUC of 0.8 (plasma) and 0.9 (CSF). Characteristics of the metabolites indicate perturbations in the glycerophospholipid, sphingolipid, and amino acid metabolism in PD, which underscores the high power of metabolomic approaches. Further studies will enable to develop a potential metabolite-based biomarker panel specific for PD.

Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: altered mitochondrial and energy metabolism

“…Studies of cerebrospinal fluid (CSF) from patients with PD have identified PD-specific alterations in several metabolic pathways, including polyamine metabolism, the purine, pyruvate, kynurenine pathways, and redox markers (31,(33)(34)(35)(36). Although there is growing interest in the use of metabolomics in PD research, many of these studies do not corroborate each other possibly due to low sample numbers, clinical heterogeneity, and different analytical approaches (30).…”

DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs)

“…PD patients might suffer from dysfunction of the transport of neutral and basic amino acids across the blood-brain barriers (85). Changes in amino acid metabolism in plasma/CSF of the patients, highlighting the role of altered amino acid metabolism and PD pathology (86). Decreased amino acid concentrations could be involved in loss of microbial proteases/peptide catabolism (80).…”

Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7

“…Apart from the CAG repeat length, environmental and genetic modifiers might contribute to SCA7 pathophysiology [8]; thus, identification of sensitive biomarkers will facilitate the monitoring of disease progression and assessing of treatments, which ultimately will improve clinical management of patients. Metabolomics has emerged as a powerful technique to identify potential biomarkers in neurodegenerative diseases [19][20][21] as alterations in brain function can be reflected in the metabolite composition of biofluids such as the serum, plasma, and cerebrospinal fluid (CSF) [22][23][24]. Indeed, recent reports have described the detection of some neurometabolites associated with specific changes in neuronal and astrocytic cells in patients with different SCAs [25].…”