Plasma Metabolite Signature Classifies Male LRRK2 Parkinson's Disease Patients.

Chen Dong,Elizabeth M O’Day,Matthew Surface,Keri B Sheehan,Chandrashekhar Honrao,Leonardo O Rodrigues,Josephine Wolf,Roy N Alcalay

doi:10.3390/metabo12020149

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease, causing loss of motor and nonmotor function. Diagnosis is based on clinical symptoms that do not develop until late in the disease progression, at which point the majority of the patients’ dopaminergic neurons are already destroyed. While many PD cases are idiopathic, hereditable genetic risks have been identified, including mutations in the gene for LRRK2, a multidomain kinase with roles in autophagy, mitochondrial function, transcription, molecular structural integrity, the endo-lysosomal system, and the immune response. A definitive PD diagnosis can only be made post-mortem, and no noninvasive or blood-based disease biomarkers are currently available. Alterations in metabolites have been identified in PD patients, suggesting that metabolomics may hold promise for PD diagnostic tools. In this study, we sought to identify metabolic markers of PD in plasma. Using a 1H-13C heteronuclear single quantum coherence spectroscopy (HSQC) NMR spectroscopy metabolomics platform coupled with machine learning (ML), we measured plasma metabolites from approximately age/sex-matched PD patients with G2019S LRRK2 mutations and non-PD controls. Based on the differential level of known and unknown metabolites, we were able to build a ML model and develop a Biomarker of Response (BoR) score, which classified male LRRK2 PD patients with 79.7% accuracy, 81.3% sensitivity, and 78.6% specificity. The high accuracy of the BoR score suggests that the metabolomics/ML workflow described here could be further utilized in the development of a confirmatory diagnostic for PD in larger patient cohorts. A diagnostic assay for PD will aid clinicians and their patients to quickly move toward a definitive diagnosis, and ultimately empower future clinical trials and treatment options.

Highlights

Introduction published maps and institutional affilParkinson’s disease (PD) is a chronic, progressive neurodegenerative disease that causes devastating loss of motor and nonmotor function over time
Metabolites were extracted from plasma samples collected from patients diagnosed with PD with a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation (N = 46 cases) and non-PD approximately age/sexmatched controls without LRRK2 mutations (N = 65 controls) (Table S1)
Using a Kruskal–Wallis (KW) test for significance, we identified 18 metabolite resonances with intensity values that were significantly different (p < 0.05) between male cases and controls (Figure 1A,B), in which 11 resonances were increased and 7 decreased in the PD patients compared to the non-PD controls

Summary

Introduction

Introduction published maps and institutional affilParkinson’s disease (PD) is a chronic, progressive neurodegenerative disease that causes devastating loss of motor and nonmotor function over time. PD is the second-most common neurodegenerative disorder after Alzheimer’s dementia, with over 6 million people affected worldwide [1,2]. The diagnosis is based on clinical assessment of symptoms, and there are no blood-based biomarkers to diagnose the disease. Bradykinesia, rigidity, and resting tremor are the primary clinical indications suggestive of PD. Most patients do not exhibit these symptoms until 5–10 years after the neuropathology develops, at which point it is estimated that 80% of their dopaminergic neurons are lost [3]. PD remains challenging to diagnose due to comorbidities such as cerebrovascular disease, dementia, and other neurological disorders [4]. Resting tremor is a hallmark clinical feature of PD, not all patients with pathologically confirmed PD present with it.

Methods

Results

Discussion

Conclusion