Early diagnosis of Parkinson’s disease: A cross-species biomarker

Abstract

Background: Care management of Parkinson disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression. Methods: We investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. Results: Our translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. Conclusion: From our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance.

Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson’s Disease

“…Strikingly, abnormally high levels of pyruvate have been observed in PD patients [15,17,18], reflecting alteration in its metabolism. Consistently, using nuclear magnetic resonance (NMR)-based metabolomics in a recent study combining three different PD animal models and two independent PD patients cohorts, we have identified a set of metabolic dysregulations which strongly suggest that modification of pyruvate metabolism is associated with PD pathophysiology and progression [19]. In particular, glycolytic metabolites, including pyruvate, were increased whereas the TCA cycle metabolites remained stable.…”

“…In light of these observations, we hypothesized that MPC dysfunction may be the cause of the metabolic dysregulations we observed in our previous study [19], and that inhibiting MPC could therefore be neuroprotective. To validate the neuroprotective action of MSDC-0160, we first characterized its effects at a behavioral and histological level in unilateral 6hydroxydopamine (6-OHDA) PD rats.…”

“…Tyrosine hydroxylase (TH) immunostaining was carried out as previously described [19,32,33] on striatal and SNc sections at levels of interest (striatum: AP: +2.0/+1.6/+1.0; SNc AP: -4.8/-5.2/-5.6 related to Bregma). Briefly, after post-fixation with 4% paraformaldehyde, slices were incubated with an anti-TH antibody (mouse monoclonal MAB52 80, Millipore, France, 1: 2500) overnight at 4°C.…”

“…Blood was collected from the caudal vein under gas anesthesia with isoflurane (2%) and after 2 h of fasting, as previously described [19]. It was then stored on ice before rapid centrifugation at 1600g for 15 min at 4° C. The supernatant serum was removed and stored at -80°C until the day of NMR.…”

“…This suggests that cytosolic glycolysis and mitochondrial TCA cycle are decoupled, impacting the supply of energy. Concomitantly, ketone bodies and amino acids were increased, suggesting that other fuel sources were being used to maintain the TCA cycle [19].…”