Proteins in the cerebrospinal fluid that were seen as possible diagnostic biomarkers of Parkinson’s disease cannot serve in this role, because they lack robustness and reproducibility in earlier stages of the disease, a study has found.
The study, “Evaluation of cerebrospinal fluid proteins as potential biomarkers for early stage Parkinson’s disease diagnosis,” was published in PLOS One.
Parkinson’s is a chronic and progressive neurodegenerative disorder, mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control. It is typically diagnosed based on the presence of motor symptoms, but these can be difficult to determine as disease-causing in Parkinson’s earlier stages.
Previous studies have suggested that specific proteins in the cerebrospinal fluid (CSF) — which circulates in the brain and spinal cord — could work as early signals, or biomarkers, of disease to assist in a diagnosis. But CSF proteins have never been fully validated as Parkinson’s biomarkers in a clinical setting.
Researchers in Belgium, Germany, and the U.K. tested the suitability of 15 CSF proteins proposed as potential biomarkers for an early stage Parkinson’s diagnosis.
The panel of proteins explored were beta-amyloid (Aβ40 and Aβ42), alpha-synuclein (α-syn), tau (p-Tau and t-Tau), neurofilament light chain (NFL), interleukin 6 (IL-6), protein deglycase (DJ-1), S100β (a calcium-binding protein), osteopontin (OPN), high-mobility group box 1 (HMGB1), ubiquitin carboxyl-terminal esterase L1 (UCHL1), Fms-related tyrosine kinase 3 ligand (FLT3LG), matrix metalloproteinase 2 (MMP2) and apolipoprotein A-I (ApoA1).
Researchers began by measuring the levels of these CSF proteins in a group of 80 patients with early stage disease and 80 healthy people serving as controls. Out of the 15 CSF proteins tested, six — α-syn, DJ-1, Aβ42, S100β, p-Tau and t-Tau — were significantly dysregulated among patients.
“Aβ42, t-Tau, p-Tau, α-syn and DJ-1 were decreased in early clinical PD [Parkinson’s disease] patients compared to the controls, whereas S100β levels was increased in early clinical PD patients,” the researchers wrote.
To confirm these candidates, researchers next performed this same test in an independent group of 30 Parkinson’s patients with advanced disease and 30 healthy controls. Here, a type of beta-amyloid, Aβ42, was the only CSF protein whose levels were significantly different — significantly lower — in Parkinson’s patients compared to controls.
“Decreased Aβ42 levels in CSF samples from PD patients had been reported recently, suggesting it may be a reliable candidate. However, in this study … analysis showed that this potential marker was not suitable for diagnostic purposes,” the researchers wrote.
Finally, to assess whether a combination of these markers could distinguish early Parkinson’s patients from healthy individuals, they used a machine learning approach based on an algorithm to identify markers that might improve disease diagnosis. Based on this model, a set of markers comprising α-syn, S100β, and UCHL1 were identified as promising candidates.
“[T]his model aligned with findings published in the literature, where α-syn is characterized as the hallmark protein of PD, closely involved in the progression of neuronal degeneration and subsequent motor impairments, while S100β has been considered a possible marker for the accompanying neurodegeneration,” the researchers wrote. However, “the decision tree could not be confirmed” in the second group of patients and controls.
“[C]urrently proposed protein CSF markers for PD diagnosis, as identified in late stage PD cohorts, lack robustness and reproducibility when applied in the early clinical stages of (…) PD,” they added.
The researchers believe that further efforts, including the EU-BIOMARKAPD project that is exploring alternative approaches to biomarker identification, may support the development of potential protein CSF biomarkers for clinical diagnosis or disease monitoring in early stage Parkinson’s disease.
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