MicroRNAs as diagnostic biomarkers of Parkinson's disease

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is a heterogeneous disease caused by the complex interactions between genetic and environmental risk factors. The cardinal motor features of PD include a resting tremor, bradykinesia and rigidity. However, this disease presents with a wide variety of other motor and non-motor symptoms, which contribute significantly to the disability, morbidity and mortality associated with PD. The current gold-standard for the diagnosis of PD is neuropathology. Although clinical diagnostic criteria have helped standardize and improve diagnosis, they are heavily dependent on the expertise of the diagnostician and might not be appropriate for patients in early stages who do not yet meet the required thresholds for diagnosis. The need to identify patients in early and presymptomatic stages of the disease is fundamental to developing novel disease-modifying therapies. As clinically evident PD is associated with a significant loss of dopaminergic neurons in the basal ganglia, along with widespread neural network dysfunctions, identifying patients at this stage limits the impact of novel neuroprotective and disease-modifying therapies. There is, therefore, an urgent, unmet need for biomarkers which allow for the early and accurate diagnosis of PD, detect disease progression and facilitate the discovery of novel therapies. A promising class of biomarkers which are easily and non-invasively obtained from several biofluids are microRNAs (miRNAs). This study aimed to identify plasma miRNAs which are able to discriminate between PD patients and controls with high diagnostic certainty. Plasma-derived miRNA signatures were identified from patients in relatively early disease stages (miR-451a, miR-151a-5p and miR-223-3p) and at a later disease stage (miR-195-5p and miR-423-3p). Both these miRNA signatures were able to discriminate between patients and controls with good diagnostic accuracy. Moreover, the high specificities of these signatures also demonstrates good ability to identify unaffected individuals and therefore serve as potential screening tests. Pooling data from this study into a larger meta-analysis also demonstrated good diagnostic accuracy indices, helping to strengthen the evidence that biofluid miRNAs are capable of effectively discriminating between PD patients and controls with high diagnostic certainty. Additionally, miRNAs which correlated with specific clinical features of PD were also identified. For example, miR-130b-3p, which correlated with cognitive assessment scores, suggesting a potential role for this miRNA to serve as a specific marker for cognitive impairment in PD. Additionally, several novel miRNAs (miR-7-1-3p, miR-25-3p, miR-27b-3p, miR-30e-5p, miR-151a-3p, miR-151a-5p, miR-301a-3p, miR-378a-3p, and miR-484) were identified in the plasma of PD patients compared to controls, which merit further validation and exploration into their role in disease pathology and their potential to serve as novel therapeutic targets for PD. In summary, miRNAs could be considered as promising candidate peripheral biomarkers of PD. The advantages of being able to repeatedly and easily access blood as part of routine clinical investigations cannot be overstated. Furthermore, the cost-effectiveness of blood tests would allow them to be widely used in clinics of most economic backgrounds. Additionally, it would also enable testing in patients who present to primary care with prodromal symptoms which are commonly associated with PD, making this a potentially effective way to identify patients in very early stages of the disease. Beyond the clinic, an objective diagnostic measure to confirm a clinical PD diagnosis would also be crucial for drug trials needing to homogenize and stratify their cohorts to help facilitate the development of DMTs and further our understanding of the pathology of PD