As part of our commitment to advancing the diagnosis, treatment and prevention of Parkinson’s disease (PD), The Michael J. Fox Foundation has launched an update of our Parkinson’s Biochemical Biomarkers Pipeline Report.
Biochemical biomarkers are measurable molecules, like proteins or enzymes, that allow researchers and healthcare providers to test for presence of disease, indicate progression of that disease and monitor how well a treatment is working, or is not working. As an example, a cholesterol test can be used to diagnose high cholesterol, indicating high risk for heart disease or stroke, and then to see how well a statin medication is working to lower overall cholesterol levels.
Alpha synuclein (aSyn), the protein that clumps in the brains of people with Parkinson’s, is one known biochemical biomarker for the disease. But it is just one of many under investigation by researchers. Others include biomarkers related to Parkinson’s-relevant gene mutations and dysfunction in disease-related pathways including mitochondrial, lysosomal and immune pathways.
“Biomarkers may have many different applications,” said Ariana Farrand, PhD, MJFF senior scientific portfolio manager. “For example, in clinical trials for Parkinson’s, they can be used to identify someone who has the disease, subgroups of patients that may be more likely to respond to a particular type of treatment or to measure how someone responds to treatment. They may also be used to identify people with Parkinson’s early in their disease progression, with the goal of one day slowing or halting the disease before symptoms even start.”
The Parkinson’s Biochemical Biomarkers Pipeline Report builds upon MJFF’s commitment, through our Strategic Research Agenda, to better define and diagnose Parkinson’s disease, as well as make clinical trials testing new therapies faster and more efficient. By publishing this report annually, MJFF consolidates critical information in an easily digestible format for the research community.
Shaping the Strategic Approach to Biomarkers
MJFF is using the Parkinson’s Biochemical Biomarkers Pipeline Report to identify opportunities for advancing Parkinson’s biomarker research and to track promising biomarkers as they move toward use in clinical studies.
The report identifies which biochemical biomarkers have reached early qualification — meaning enough scientific evidence exists to support their use in the following key areas of Parkinson’s research:
Diagnosis: Detecting or confirming the presence of Parkinson’s disease
Prognosis: Predicting disease progression and what types of symptoms may develop
Prediction: Identifying who might benefit from certain treatments, helping researchers to select clinical trial participants
Susceptibility and Risk: Assessing the likelihood of PD developing in people who do not currently have symptoms
Disease Monitoring: Tracking changes in the condition over time, from the earliest signs of PD to newly diagnosed and advanced stages of PD
Pharmacodynamics: Measuring biological response treatments, including disease-modifying therapies in clinical trials
The report is a practical resource for MJFF research partners or external scientists interested in biomarker development and serves as a reference point for developing therapeutic trials, helping researchers know which specific biomarkers to target.
“For the Foundation’s purposes, it has been quite helpful in identifying potential gaps in research that MJFF could address through strategic funding,” said Dr. Farrand.
Biomarkers in the Pipeline
“Researchers continue to study potential biomarkers for PD, such as immune, lysosomal (breakdown of cellular recycling and degradation systems) or mitochondrial dysfunction (the breakdown of cells’ energy production). Developing biomarkers for these pathways may help people more accurately define their personal PD biology and are especially important as more and more therapeutics in the pipeline specifically target these cellular pathways,” said Dr. Farrand.
If researchers can identify biomarkers for specific disease pathways, this could eventually allow treatments to be tailored to different subgroups of patients, similar to how types of cancer each require their own therapy.
Some of the latest developments in PD biochemical biomarkers are detailed in the report and include the following:
Alpha-synuclein: In 2023, scientists using data from the Parkinson’s Progression Markers Initiative (PPMI) validated a biological test that uses a spinal tap to detect misfolded aSyn in cerebrospinal fluid. Researchers are actively investigating less invasive ways to collect aSyn from blood, skin, tears, saliva, salivary glands, nose and the gastrointestinal tract. They are also measuring total levels of aSyn in the body, modified forms of the protein, aSyn attached to fats, and aSyn carried by extracellular vesicles, which are tiny particles that carry proteins released by cells. Finding new, better, and less invasive ways to assess aSyn could help researchers measure and track PD over time, a goal of MJFF’s Quantitative Biomarkers Program (QBio.)
GBA1 gene mutations: This gene carries instructions for producing the enzyme glucocerebrosidase (GCase), which helps break down lipids or fats. GBA1 gene mutations can disrupt this process and are the most common genetic risk factor for PD. Restoring lipid balance may be important for healthy cell function, and medications that target GCase are currently in clinical trials. Recently, researchers identified a variant in the GBA1 gene in people of African ancestry, a finding that may expand the use of GBA1-targeted therapies to this underrepresented population and encourage the development of new treatments. Further research opportunities include finding better ways to accurately measure GCase in cerebrospinal fluid and the blood and developing a deeper understanding of lipids and their role in PD.
LRRK2 gene mutations: The LRRK2 gene produces an enzyme that helps manage intracellular communication and waste clean-up. Mutations in this gene can overactivate the enzyme, leading to cellular dysfunction. LRRK2 mutations are the most common genetic cause of inherited PD and are also found in non-inherited PD. The LRRK2 Investigative Therapeutics Exchange (LITE) is deeply characterizing biomarkers related to LRRK2 in people with genetic mutations around the world to support LRRK2-based therapies.
Inflammation and immune regulation: Increased inflammation in the brain is observed in PD and has been linked to aSyn clumping. Changes in immune system genes, which produce proteins that recognize harmful substances in the body, are associated with increased inflammation and PD risk. Researchers are developing ways to standardize measurements and improve testing of immune system proteins (which normally appear in low levels in fluids and may be impacted by a number of factors unrelated to PD), to help advance this area of scientific investigation.
Mitochondrial dysfunction: Long-term exposure to environmental toxins may damage mitochondria and contribute to increased PD risk. Identifying biomarkers associated with this damage could help with the development of targeted therapies and early identification of individuals at high risk for developing PD due to mitochondrial damage. Scientists are trying to address limitations associated with measuring this damage as well as developing new assays to measure mitochondrial function in different ways.
Neurodegeneration: Several neurodegeneration biomarkers, such as clumping of proteins other than aSyn, have been studied in Alzheimer’s disease and may be useful in predicting cognitive outcomes in people living with PD. Continuing to leverage validated neurodegeneration assays to evaluate relevant PD cohorts will support future expansion of the Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS), a research framework that defines disease based on the presence of aSyn and dopamine dysfunction.
Next Steps for Biomarker Research
Immediate next steps for biomarker research at the Foundation include continuing to develop and push more promising biomarkers through the pipeline.
“Our ultimate goal is getting these markers ready for use in clinical trials as quickly as possible,” said Dr. Farrand.