A metabolic biomarker predicts Parkinson’s disease at the early stages in patients and animal models
David Mallet, … , Florence Fauvelle, Sabrina Boulet
David Mallet, … , Florence Fauvelle, Sabrina Boulet
Published December 16, 2021
Citation Information: J Clin Invest. 2022;132(4):e146400. https://doi.org/10.1172/JCI146400.
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Clinical Research and Public Health Metabolism Neuroscience

A metabolic biomarker predicts Parkinson’s disease at the early stages in patients and animal models

Abstract

Background Care management of Parkinson’s disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.Methods We investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). 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, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.Conclusion From our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.Funding French National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.

Authors

David Mallet, Thibault Dufourd, Mélina Decourt, Carole Carcenac, Paola Bossù, Laure Verlin, Pierre-Olivier Fernagut, Marianne Benoit-Marand, Gianfranco Spalletta, Emmanuel L. Barbier, Sebastien Carnicella, Véronique Sgambato, Florence Fauvelle, Sabrina Boulet

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Figure 2

Striatal dopaminergic denervation induced by bilateral 6-OHDA lesion of the SNc leads to apathetic-like behavior and fine motor dysfunctions.

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Striatal dopaminergic denervation induced by bilateral 6-OHDA lesion of ...
(A) A PDP total score, as the sum of histological and behavioral components, was assigned to each animal, from 0 (sham-operated animal) to 3 to 7 (prodromal-like animal) or 8 to 12 (clinical-like animal). (B) Examples of TH-stained coronal sections of sham-operated and 6-OHDA rat brains at 3 striatal levels with respect to bregma and corresponding diagrams selected from the atlas of Paxinos and Watson (79), with areas used for quantification of dopaminergic denervation. Scale bar: 2 mm. (C) Quantification of TH-IR staining loss at the striatal levels shown in B, expressed as a percentage of the mean value obtained for sham-operated animals (n = 22). We observed a large decrease of TH-positive neurons in DS and a lighter decrease in Nacc of prodromal (n = 14) and clinical-like (n = 15) rats. (D) 6-OHDA SNc lesion induced an abrupt instrumental deficit in an operant sucrose self-administration procedure. Results are expressed as the mean number of sucrose deliveries per session. Sham-operated rats (n = 22); prodromal-like rats (n = 14); clinical-like rats (n = 15). (E) 6-OHDA SNc lesion reduced the number of adjusting steps in a stepping procedure only in clinical-like animals. Results are expressed as the mean number of forelimb adjustments for 2 trials before (left bars) and after (right bars) 6-OHDA (prodromal-like (n = 14) and clinical-like (n = 15) animals or saline (sham) injection (n = 22). Data are presented as mean ± SEM and were determined by 1-way ANOVA or RM-ANOVA followed by Tukey’s post hoc or Šidák’s test. ***P ≤ 0.001, compared with sham-operated animals; ##P ≤ 0.01, clinical-like compared with prodromal-like; #P < 0.05; §§§P ≤ 0.001, before surgery compared with after surgery.