In Parkinson’s disease, a-synuclein, a protein in the brain, suddenly starts to aggregate and form larger structures called amyloid fibrils. a-synuclein normally plays a vital function in the brain, where it ensures that neurons can send signals to other neurons. However, when the protein begins to form fibrils inside a neuron, several cellular processes are disturbed and the neuron loses its function. Eventually it degenerates - it simply dies.

“The a-synuclein aggregates are formed inside many neurons in the brain and this affects their function. Among the neurons, those producing dopamine in the midbrain are especially susceptible. This is why Parkinson’s disease can be accurately diagnosed when the brain is scanned for dopamine activity. As the disease progresses the dopamine level becomes lower,” explains Marina Romero-Ramos.

This decrease of dopamine is associated to the well-known symptoms of Parkinson’s disease, such as the shaking of hands, the slow and rigid movements and poor balance. But the accumulation of fibrils in other neurons contribute to the many additional symptoms in the disease such as, constipation, depression, sleep problems, and dementia. In fact, these non-motor symptoms can appear earlier in the disease than the characteristic motor problems. As Marina Romero-Ramos clarifies: “The disease is in fact much more than a motor disorder. We should rather consider it a multisystem disorder where the immune system is also involved.”

Observation of the motor symptoms is the common strategy for the diagnosis and follow up of people with Parkinson’s disease. But this requires long clinical testing, and relies on the evaluation of many subjective parameters, both from the point of view of the patient, but also from the physician observing the patient.

Brain scans is an objective diagnostic method that can also be used to assess the loss of neuronal function in people with Parkinson’s disease, and hence how far the disease has progressed. However, this is both an expensive and time-consuming approach. Marina Romero-Ramos and the IMPAD team were thus keen on identifying objective biomarkers in the blood of people with Parkinson’s disease: “It only takes a few minutes to take a blood sample. It would be a huge step forward, if we can use blood samples to inform about the disease and its stage and better decide on the best therapy for each patient individually. We are also hoping that the blood sample can reveal novel targets for treating the disease - maybe even with already existing immune-related drugs,” she says.

To get an in-depth understanding of how the immune system changes during the onset and progression of Parkinson’s disease, the IMPAD team used a parallel approach: Clinician Per Borghammer, who proposed the two subtypes of Parkinson’s disease, has 18 years of experience with the disease. He collected blood samples from people with Parkinson’s and evaluated the patients both clinically and by brain scans. When the blood samples arrived in Marina Romero-Ramos’ lab, two different analyses were performed. “My team analyzed the different immune cells and their expression of genes in the blood samples. Jørgen Kjems’ team performed an analysis on the same samples to clarify the protein expression profiles. In this way, we correlated the well-characterized groups of people with Parkinson’s disease, where we have information about what groups of neurons are affected, directly with the changes in immune cells and potential biomarkers,” says Marina Romero-Ramos.

The collection of samples from people with Parkinson’s was a complex and time-consuming process. The IMPAD team is currently analyzing the last samples and so far, the results indicate that significant changes occur in the cells of the innate and adaptive immune system during disease. “We see different gene expression patterns when we compare for instance the two subtypes of Parkinson’s disease. There is also a difference between early and late disease stages within a single subtype,” explains Marina Romero-Ramos.

While analyzing the gene expression pattern of the immune cells, the protein expression pattern of the same blood samples was compared between the different sample groups in the lab of Jørgen Kjems. The individual protein profiles of groups of people with Parkinson’s differed significantly from that of healthy persons. These findings indicate that blood is a good and accessible bio-sample for objective diagnosis and follow up of the people with Parkinson’s.

“When all samples have been analyzed, we hope to have a thorough characterization of how the immune cell representation changes over the course of the disease. This knowledge can form the basis for identifying new therapeutic drugs. Immunotherapy might thus be a relevant avenue of research when it comes to Parkinson’s disease,” says Marina Romero-Ramos. “If we succeed in finding specific biomarkers that can inform on disease stage and neuronal changes in the brain, these biomarkers can be used for both diagnosis but also – and just as importantly – for objective evaluation of efficacy, when testing new drugs,” she concludes.

“The IMPAD project has opened many new roads for us: we want to understand the relevance of the cellular differences between the disease subtypes and if they can be used to modify the disease. In that regard, the studies in the human cellular models performed in Lundbeck H.  and the animal models developed here at Aarhus University, will also help us to choose the most appropriate model for our future studies”. Dr. Romero-Ramos has recently obtained an Ascending Investigator from Lundbeck Foundation that will allow her lab to continue her research on the relevance of the vagus nerve in the disease. “In addition, since Per Borghammer is following the patients’ progression, in a couple of years we will be able to interrogate whether some of the parameters we have measured now, can be used to predict if a patient will progress faster or not.”

You can read more about the IMPAD project here.