Elemental fingerprint: Reassessment of a cerebrospinal fluid biomarker for Parkinson's disease

Abstract

The aim of the study was to validate a predictive biomarker machine learning model for the classification of Parkinson's disease (PD) and age-matched controls (AMC), based on bioelement abundance in the cerebrospinal fluid (CSF). For this multicentric trial, participants were enrolled from four different centers. CSF was collected according to standardized protocols. For bioelement determination, CSF samples were subjected to inductively coupled plasma mass spectrometry. A predefined Support Vector Machine (SVM) model, trained on a previous discovery cohort was applied for differentiation, based on the levels of six different bioelements. 82 PD patients, 68 age-matched controls and 7 additional Normal Pressure Hydrocephalus (NPH) patients were included to validate a predefined SVM model. Six differentiating elements (As, Fe, Mg, Ni, Se, Sr) were quantified. Based on their levels, SVM was successfully applied to a new local cohort (AUROC 0.76, Sensitivity 0.80, Specificity 0.83), without taking any additional features into account. The same model did not discriminate PD and AMCs / NPH from three external cohorts, likely due to center effects. However, discrimination was possible in cohorts with a full elemental data set, now using center-specific discovery cohorts and a cross validated approach (AUROC 0.78 and 0.88, respectively). Pooled PD CSF iron levels showed a clear correlation with disease duration (p = .0001). In summary, bioelemental CSF patterns, obtained by mass spectrometry and integrated into a predictive model yield the potential to facilitate the differentiation of PD and AMC. Center-specific biases interfere with application in external cohorts. This must be carefully addressed using center-defined, local reference values and models.

Keywords: Biomarker; Cerebrospinal fluid; Iron; Parkinson's disease.