A metabolic biomarker predicts Parkinson’s disease at the early stages in patients and animal models
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
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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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 6

Alternative PD models from different animal species show similar metabolic dysregulations in serum.

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Alternative PD models from different animal species show similar metabol...
(A) Score plot of the OPLS-DA model built with 1HNMR spectra of serum samples from α-synuclein rats versus first predictive and first orthogonal components (α-synuclein OPLS model). Three groups are clearly discriminated, mimicking 3 different stages of PD (sham operated, n = 12; prodomal-like, n = 11 clinical-like n = 11). R2Y = 0.929; Q2 = 0.518; 1 predictive and 3 orthogonal components; CV ANOVA, P = 0.008. (B) Relative amplitude of most discriminating metabolites in the α-synuclein OPLS model, i.e., acetoacetate, betaine, BHB, creatine, glycine, myoinositol (myo), pyruvate,and serine in sham-operated (n = 12), prodromal-like (n = 11), and clinical-like (n = 11) animals. (C) Score plot of the OPLS-DA model built with 1HNMR spectra of serum samples from nonhuman MPTP primates versus first predictive and first orthogonal components (MPTP OPLS-DA model). Sham-operated (n = 6) and clinical-like (n = 8) animals are clearly discriminated. R2Y = 0.998; Q2 = 0.963; 1 predictive and 1 orthogonal component; CV ANOVA P = 0.0005. (D) Relative amplitude of most discriminating metabolites in the MPTP OPLS-DA model, i.e., acetoacetate, alanine, betaine, BHB, creatine, lactate, pyruvate, and valine in sham-operated (n = 6) and MPTP (n = 8) animals. Data are represented as mean ± SEM, mixed model followed by Tukey’s post hoc test or Mann-Whitney test. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.