New blood test for diagnosing early stage Parkinsons Disease

Pre Diagnostics will develop a non-invasive blood test for detection of Parkinson’s Disease (PD) in the early disease stage. This will enable diagnosis and treatment in an earlier phase than today’s diagnostic gold standard allows. PD is the second largest neurodegenerative disease. By the time PD is diagnosed, 60-70% of a patient’s PD relevant brain neurons are affected, causing well-known symptoms such as shaking, stiffness and slow movements (the “cardinal symptoms”). Current treatments offer some relief, but new and promising treatment candidates are under development. For these to have full effect, new methods to detect PD at an earlier stage is required. Today’s diagnostic routine entails a lengthy review of medical history coupled with a battery of neurological tests. The disease is generally considered difficult to diagnose as many symptoms are shared with other disorders, but if two or more of the cardinal symptoms are present, PD is generally diagnosed. Our concept is based on the hypothesis that PD evokes disease-specific responses in immune cells, manifesting in reduced clearance of the protein “alpha-Synuclein”. PD patient’s clearance mechanism is hampered, leading to accumulation of protein over time, eventually also causing cell death. Our test will measure a person’s clearance capacity for this toxic protein. During the first year of this project, Pre Diagnostics will develop an automated method for isolation of immune cells from blood samples. In addition, blood samples will be collected from PD patients and healthy controls for a pilot project. Advanced technologies will be applied to identify breakage pattern of alpha-Synuclein which are deviating between PD and healthy controls.

The present project aims to develop a preclinical blood test for Parkinson’s Disease (PD) by identifying intra-cellular fragments of disease-causing proteins. PD is a neurodegenerative disease characterized by motor symptoms and eventually cognitive defects. A massive neurodegeneration has occurred upon initial clinical diagnosis. Currently no early, specific and definitive analytical test exists. An ideal biomarker should be directly related to the disease development. The protein alpha Synuclein (a-Syn), central in neurotransmitter release, is widely considered to be such a marker. Due to extensive Post Translational Modifications (PTMs), Total a-Syn in plasma and CNS has failed as a clinically relevant biomarker. The innate immune system plays a pivotal role in clearance of toxic proteins and is an essential feature of PD development. Our patented diagnostic concept, already proven in Alzheimer's Disease, is that neurodegenerative diseases evoke systemic responses in innate immune cells, impacting protein clearance. Our test will quantify a-Syn clearance in blood monocytes. The biomarker is therefore directly linked to the underlying pathological process of PD. Together with our R&D provider Ahus, we will study a-Syn clearance in patient-derived monocytes, in monocyte cell lines and in in-culture microglial cells (hiPSC) documenting clearance patterns. Less PTMs of a-Syn are expected in monocytes as opposed to in plasma and CSF. Identification of disease specific peptides will be critical for all downstream development in this project. A preliminary set of peptides separating PD from healthy controls has been identified (feasibility study), demonstrating potential for further identification of disease-relevant peptides by analysing more samples with IP-LCMS before final selection of the peptides for the diagnostic assay.? We predict that clearance of a-Syn in the peripheral blood monocytes reflects clearance in the CNS and is linked to the PD disease process.