New Research for a Parkinson’s Biomarker

Exciting Parkinson’s disease (PD) news was announced last week, based on a newly published medical research study. The article reported on the results of using an established test on cerebral spinal fluid to detect abnormal alpha-synuclein as a way of confirming the diagnosis of PD and even diagnosing PD at very early stages, before motor symptoms develop.

The test is called Seed Amplification Assay, developed by Amprion, under the name of SynTap, and here is how it works:

Many researchers believe that what underlies the development of PD is the misfolding of a normal protein called alpha-synuclein. Evidence suggests that misfolded molecules of alpha-synuclein can induce their neighbors to misfold, causing a cascade that eventually leads to aggregation or accumulation of abnormal alpha-synuclein. Clumps of misfolded alpha-synuclein build up in the brain and interfere with the normal functioning of the brain cells, eventually causing cell death. The process of misfolding is believed to start years or even decades before the appearance of clinical symptoms of PD.

Interestingly, these misfolded proteins are not only found in the brain, but can also be found in body fluids such as cerebrospinal fluid (CSF) and blood, before clinical symptoms develop, and therefore it has been the hope that detection of the misfolded protein could be used as biomarkers for early diagnosis of these diseases.

However, the quantities of these abnormal protein collections present in body fluids are very low. Therefore, new methods needed to be invented to detect them effectively and reliably. A test called the Seed Amplification Assay (SAA) has been developed to detect abnormal aggregates of alpha-synuclein. Of note, this approach is very similar to other assays known by the names of Protein Misfolding Cyclic Amplification (PMCA) and Real-time Quaking Induced Conversion (RT-QuICR).

In the SAA test, a sample of CSF, that may or may not contain misfolded proteins, is mixed with normal proteins in defined experimental conditions. The very small amount of misfolded protein in the patient’s sample can act as a seed, triggering normally folded protein particles to misfold and aggregate in an amplification process. Once the amount of misfolded protein reaches a certain threshold, it can be detected using a fluorescent probe.

SAA was developed to detect abnormal alpha-synuclein in CSF. The test has been commercially available for more than a year and can be ordered by a physician (via self-pay only at this time). There is more misfolded protein in CSF than in blood, which makes it easier to use for detection. However, collection of CSF is more invasive than a blood test (CSF samples are obtained via a needle inserted into the fluid surrounding the spinal nerves that emerge from the bottom of the spinal cord). Research continues to try to adapt this test to be performed on blood. APDA is on the forefront of these efforts, funding Dr. Mohammad Shahnawaz in his research to develop an SAA test for PD on a blood sample.

Now how does this relate to the latest PD research news?

In the recently published paper, the SAA on CSF (the same one that is commercially available) was performed in a large group of people (via the Parkinson’s Progression Markers Initiative) and confirmed that it is a great biomarker for people with Parkinson’s disease (PD). This was not a surprising result, but more data to provide strong confirmation is always better, as it confirms what earlier research was showing and instills more confidence in the findings.

There were some additional very interesting findings in the paper. The test was also used on a group of people with prodromal, or early non-motor symptoms – REM behavior sleep disorder and poor sense of smell. These are symptoms that often develop before the motor symptoms of PD and can be considered “pre-motor symptoms”. People with these symptoms also had high rates of positivity on this test – indicating that it could be a good test to diagnose PD prior to the onset of motor symptoms. That is very exciting! The data also suggest that detection of alpha-synuclein in CSF may be positive earlier than with a DaTscan, which is an imaging test for PD.

In addition, the paper looked at the rates of positive tests in other populations such as PD related to certain genetic changes. People with PD who have a particular mutation in LRRK2 for example, are less likely to be positive for this test, which correlates with the fact that people with this mutation are less likely to have alpha-synuclein aggregation as the pathological basis for their PD. This information is important for clinical trials – if there is a therapy that disrupts alpha-synuclein aggregation, it would not be expected to help in those who do not have alpha-synuclein aggregation underlying their PD.

It is important to add that there is also a commercially available skin biopsy test to confirm a diagnosis of Parkinson’s disease. This article explores both the CSF test and the skin biopsy test. What has not been confirmed yet is whether the skin biopsy will detect pre-motor or prodromal PD. A skin biopsy is much more palatable to people than a lumbar puncture, so if it is also positive in the prodromal population, it will likely be the test to become more popular, and not the CSF test. Although the skin biopsy test is commercially available now, more research is needed to be done to ensure its reliability and define its limitations as a clinical test for PD.

As always, APDA keeps a close eye on the latest PD research, and we will bring you news as it develops.

We invite you to learn more about APDA’s research program and the work we fund.