Metabolomic investigations in cerebrospinal fluid of Parkinson's disease

Abstract

The underlying mechanisms of Parkinson´s disease are not completely revealed. Especially, early diagnostic biomarkers are lacking. To characterize early pathophysiological events, research is focusing on metabolomics. In this case-control study we investigated the metabolic profile of 31 Parkinson´s disease-patients in comparison to 95 neurologically healthy controls. The investigation of metabolites in CSF was performed by a 12 Tesla SolariX Fourier transform-ion cyclotron resonance-mass spectrometer (FT-ICR-MS). Multivariate statistical analysis sorted the most important biomarkers in relation to their ability to differentiate Parkinson versus control. The affected metabolites, their connection and their conversion pathways are described by means of network analysis. The metabolic profiling by FT-ICR-MS in CSF yielded in a good group separation, giving insights into the disease mechanisms. A total number of 243 metabolites showed an affected intensity in Parkinson´s disease, whereas 15 of these metabolites seem to be the main biological contributors. The network analysis showed a connection to the tricarboxylic cycle (TCA cycle) and therefore to mitochondrial dysfunction and increased oxidative stress within mitochondria. The metabolomic analysis of CSF in Parkinson´s disease showed an association to pathways which are involved in lipid/ fatty acid metabolism, energy metabolism, glutathione metabolism and mitochondrial dysfunction.

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

“…Alterations in levels of TCA cycle metabolites have been reported previously in relation to PD. For instance, an increased malate concentration was found in plasma (49), and an increased citrate concentration in the CSF (50) of PD patients. In contrast, decreased levels of several TCA metabolites (citrate, malate, succinate, and isocitrate) have also been detected in brains from PD patients (51).…”

Bacterial Metabolites Mirror Altered Gut Microbiota Composition in Patients with Parkinson’s Disease

“…Therefore, many studies focused on metabolic biomarker screening (comparing healthy subjects with either familial PD or idiopathic PD), for an early detection of potential development of PD. The metabolic profiles of PD patients (in cerebrospinal fluid (CSF), blood or urine) usually reflect oxidative stress [24,[27][28][29][30][31] or mitochondrial dysfunction [24,[31][32][33][34][35]. However, many studies also observed differences in metabo-lites from bacterial origin, which are summarized in Table 2.…”

“…Taken together, data available suggest that altered levels of IAA, which are caused by changes in microbial composition, might play a role in attenuating inflammation in PD patients. p-Cresol sulfate (sulfonated by the liver), which is exclusively produced by gut bacteria [53], mainly by species belonging to Clostridiaceae (Clostridium clusters I, IV, IX, XI, XIII, XIVa, XVI) and Bacteroidaceae families [54] (Table 1), is also observed to be ∼10 fold increased in in the CSF of PD patients [31] but not in blood samples [24,28]. However, differential metabolite levels in blood do not necessarily reflect CSF levels [55].…”

Gut Microbiota and Metabolome Alterations Associated with Parkinson’s Disease

“…Moreover, gut microbiota modifications could reflect changes in bacterial metabolites. To date, several studies have investigated the metabolomics profile of PD patients in different biological samples, such as cerebrospinal fluid, blood, and urine (21)(22)(23)(24)(25)(26). However, only a few studies have explored the fecal metabolome that mirrors the status of colonic bacteria and also links the symbiotic microbiota and health.…”