Unlocking early Parkinson's detection: the power of blood-based biomarkers

Unlocking early Parkinson’s detection: the power of blood-based biomarkers

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Today, Parkinson’s Disease (PD) is still diagnosed by a visual examination of a patient’s physical symptoms (tremor, rigidity, bradykinesia). These physical symptoms only begin to appear after a large number of the crucial dopamine-producing cells in the brain have already been lost. Due to the degenerative nature of PD, more and more of these cells will continue to be lost over time. If early detection of PD was possible, it could alter the course of the disease entirely and allow patients to begin treatment before the onset of major symptoms.

The mitochondrial DNA biomarker

Researchers have identified a marker that could indicate Parkinson’s in its early stages. This so-called “blood biomarker” focuses on DNA found in the mitochondria. The mitochondria, located in each cell of our body, provide the energy necessary for a cell’s survival. Mitochondrial dysfunction has been established to be a mechanism leading to the progression of PD, and patients with PD have been shown to have mutations or damage in mitochondrial DNA in lab analysis. As mitochondrial DNA is important to cellular processes, a test that can identify mitochondrial dysfunction would be key to understanding more about PD progression. Furthermore, mutations in a gene implicated in PD (called LRRK2) have been linked to mitochondrial DNA damage. Therefore, understanding mitochondrial DNA damage can also serve as a surrogate marker for alterations in the LRRK2 protein activity.  

The mitochondrial DNA damage assay (Mito DNADX) essentially targets mitochondrial DNA, amplifies it, and quantifies it. The idea is that less product will be produced in the assay if there is mitochondrial DNA damage because the damaged portions won’t amplify properly. The test targets the presence of damaged mitochondrial DNA and can quantify the level of damage to potentially track the disease over time.  

To compare the effectiveness of the conventional assay and the novel MitoDNADX assay, cells were treated with a DNA-damaging agent and the levels of mitochondrial damage were then measured. The conventional assay produced no difference in output when comparing controls to the damaged DNA. However, the MitoDNADX assay showed increased sensitivity and an accurate ability to detect and quantify mitochondrial DNA damage. This test also showed specificity to PD and not global age-related neurodegeneration, as the same results were not shown when blood samples were taken from people living with Alzheimer’s.  

Blood serum α-synuclein seed amplification assay

In addition to using mitochondrial DNA damage as a marker of early PD, we can also use alpha-synuclein aggregation. We know that alpha-synuclein aggregates into Lewy Bodies in the brain, but recent evidence suggests we can detect this alpha-synuclein aggregation as an early biomarker of PD. To do this, researchers developed the alpha-synuclein seed amplification assay (SAA) as a binary measure for aggregate-prone (disease-associated) alpha-synuclein. When healthy alpha-synuclein is used in an SAA, it does not aggregate, however when disease-associated alpha-synuclein is used in an SAA, it aggregates. This gives researchers a clue that something could be wrong with the way alpha-synuclein is functioning and, in combination with other early diagnostic tools, could lead to an earlier disease diagnosis. 

Recent work has been devoted to validating the use of various patient samples in the alpha-synuclein SAA. The first patient sample that has been validated for high accuracy and sensitivity in detecting disease-associated alpha-synuclein is from cerebrospinal fluid (CSF). This was a huge milestone for PD biomarkers; however, CSF can be difficult to obtain. This has led researchers to strive for other patient samples that can yield the same level of accuracy and sensitivity. There has been significant work focused on validating the use of blood, skin, nasal swab, or submandibular gland samples, among others, but these are still in the testing/validation phases. 

In general, the alpha-synuclein SAA has very high sensitivity and specificity in identifying people with PD compared to healthy controls or even people with other synucleinopathies (including multiple system atrophy and Lewy Body dementia). This is especially true when combined with other biomarkers of Parkinson’s, including hyposmia (reduced sense of smell), REM sleep behaviour disorder, or some PD-linked mutations in genes such as GBA and SNCA. 

Parkinson Canada funded research in this space

The research into biomarkers for PD has been ongoing for years. One such research project titled “Biochemical and Pathological Characterization of Synuclein Aggregates from PD and RBD Patient Plasma” was conducted by Dr. Edward Fon at McGill University who was awarded the Parkinson Canada Pilot Project Grant in 2023.  

Dr. Fon’s project uses blood samples from PD patients and extends it to people with rapid eye movement (REM) sleep behaviour disorder (RBD). Most patients diagnosed with RBD eventually develop PD within the first two decades of diagnosis. Therefore, RBD represents a phase of PD prior to the onset of symptoms. This project aims to provide a platform for detecting biomarkers of PD in patients and to understand their evolving biology as disease progresses. Through this project, they would be able to shed light on the mechanisms leading to neuronal cell death and dysfunction which is a prominent feature of PD. 

What does the future hold with these new Blood-based tests?

These findings may indicate that the MitoDNADX assay has the potential to identify pathological PD processes before the symptom onset of the disease. For any PD intervention, we know that early treatment intervention is better. One barrier to conducting clinical trials targeting the earliest stages of PD is the lack of prodromal biomarkers. With this MitoDNADX assay, we may be able to identify PD in people very early on and conduct trials during the prodromal phase.  


Sources 

Source article: https://www.science.org/doi/10.1126/scitranslmed.abo1557?adobe_mc=MCMID%3D86369121341694017523678874202459855692%7CMCORGID%3D242B6472541199F70A4C98A6%2540AdobeOrg%7CTS%3D1694530681 

Commentary on mitochondrial blood test: 

New blood test shows promise for detecting Parkinson’s | Parkinson’s UK (parkinsons.org.uk) 

A blood test for Parkinson’s disease? | Science | AAAS 

Alternative Blood Test method – Seed amplification assay from blood serum: 

Propagative α-synuclein seeds as serum biomarkers for synucleinopathies | Nature Medicine