The Search for a Parkinson’s disease Biomarker

Biomarkers

One of the major themes in Parkinson’s disease (PD) research that you may have read about is the search for a biomarker, a measurable characteristic in the body which indicates that disease is present.

The biomarker can be a lab test, an imaging test or a clinical test. In this blog we will explore why a PD biomarker is so important to find and the necessary features that it must have in order to be useful and impactful in the diagnosis and treatment of PD.

Why are biomarkers so important for diagnosing Parkinson’s?

There are many reasons for finding a PD biomarker. Some of the most important are:

Earlier diagnosis

Currently, a PD diagnosis is based on clinical exam. This means that motor symptoms must be apparent before diagnosis is made. But it is known that the cell loss of PD begins decades before motor symptoms develop and that often certain non-motor symptoms appear first, so it is likely that you have signs that the disease is developing long before you actually get diagnosed. Diagnosing the disease earlier may allow you to take measures to improve your health earlier, and may be an essential element to developing a neuroprotective medication, a drug that slows down or reverses the nerve damage of PD. It is possible that such a medication would only work at the earliest stages of the disease.

Accurate diagnosis

Currently, there are a number of neurologic syndromes that share features of PD. While neurologists are trained to differentiate between these syndromes, a biomarker would ideally be able to distinguish between these diagnostic possibilities with more definitive certainty.

Disease monitoring

Currently there is no accurate way to determine PD progression over time beyond clinical exam. A biomarker would ideally be able to do this.

Clinical trials

Currently, there is no accurate way to determine if a clinical trial drug is changing the biology of PD beyond what is seen on clinical exam. Following a biomarker would ideally be part of a clinical trial to see what effects the treatment in having.

For a Parkinson’s disease biomarker to be really useful, it should be:

1. Found in the body very early in the disease course.
2. Quantitative (the amount of the biomarker detected should correlate with degree of disease.)
3. Able to distinguish between PD and non-PD patients, as well as between PD and all other neurologic diseases. It should be able to detect PD, and only PD, very well.

What additional biomarker characteristics are helpful?

1. Easy to access: a biomarker that can be found in the blood is better than one that has to be extracted from cerebrospinal fluid, for example.
2. Low cost: Even if it serves as a perfect biomarker, a sophisticated imaging test, for example, it may not ever become the standard of care if it is too expensive.
3. Reliable and reproducible: The test should be easily replicated and consistent from one tester or testing site to another.

Examples of potential biomarkers:

Lab test

• A substance found in any bodily fluid (e.g. blood, urine, cerebrospinal fluid, saliva) or on a biopsy of an easily obtainable tissue (e.g. skin, colon)

Imaging test

• A characteristic feature on an imaging test (e.g. MRI, Ultrasound, PET/SPECT scan)

Clinical test

• A clinical feature or combination of features that can be easily tested in a doctor’s office (e.g. smell test, pupillary reaction, distinctive and quantifiable voice or movement information)

What Parkinson’s biomarkers are available now?

There are some current biomarkers available, but each has its limitations, which is why identifying new biomarkers is essential to the future of PD. Here is an explanation of what we have now:

1. United Parkinson Disease Rating Scale (UPDRS): This is a clinical scale that most people with PD will be familiar with from their visits with their neurologists. It is a series of brief clinical tests which include assessments of facial expression, voice, tremor, slowness of movement in all four limbs, stiffness of all four limbs, posture, gait and balance. Each element gets a score and the total score serves as a quantifiable measure of the state of a person’s PD. This is the biomarker currently used in the clinic to follow disease progression and response to medication. It is also used in clinical trials to determine if an experimental medication is working.

The UPDRS has been validated and when performed correctly is generally reproducible from one clinician to another. However, the UPDRS remains less than ideal as a biomarker, since it is inevitable that there will be some variation between clinicians and their interpretation of each scenario, and it is therefore not perfectly reproducible. In addition, because the UPDRS relies on elements of the clinical exam, by definition it can’t be used to detect disease before motor symptoms are present.

2. DaTscan: DaTscan is an imaging test in current clinical use to aid in the diagnosis of PD. In this test, a radioactive tracer, Ioflupane ¹²³I, also known as DaTscan, is injected into the blood, where it circulates around the body and makes its way into the brain. It attaches itself to the dopamine transporter, a molecule found on dopamine neurons. People with PD will typically have a smaller signal on DaTscan in a part of the brain called the striatum, where the ends of the dopamine neurons are meant to be.

However, DaTscan is also not the perfect biomarker, because currently it is not quantitative and cannot tell if the disease has progressed or improved over time. In addition, although it can distinguish between PD and non-PD, and between PD and some neurologic conditions, it can’t distinguish between PD and some other parkinsonian syndromes.

3. University of Pennsylvania Smell Identification Test (UPSIT): This test presents a patient with a battery of odors that can quantify smell loss. Smell loss is extremely common in PD and typically occurs very early in disease course, often decades before motor symptoms. However, other neurodegenerative diseases can also experience smell loss, so the results of the test are not specific to PD.

What are biomarkers being researched now?

There has been an explosion of research attempting to find a biomarker for PD that can detect disease early, can quantify disease, and can distinguish PD from all other conditions, while being affordable, easy to obtain, and reproducible.

Although each avenue of research has so far been stymied by at least one of these elements, the quest continues to optimize the following possibilities, or develop new ideas. In the end, the perfect PD biomarker may turn out to be a combination of available and not-yet-available tests.

This is just a sample of ideas that are currently being pursued:

• Biopsies of the GI tract: Clumps of alpha-synuclein, the pathologic hallmark of PD, are not just found in nerves in the brain, but in many other places in the body including the nerves that line the gut. A biopsy of the GI tract (for example during a colonoscopy) is being investigated as a potential source of a biomarker. Currently, GI biopsies do not yet have high enough sensitivity (ability to correctly identify those with PD) and specificity (ability to correctly identify those without PD) to be a clinically reliable tool, but this is an evolving field.
• Exosomes: These are tiny spheres derived from cells, which can be found in many body fluids such as blood and urine. There are many theories as to what their actual function is in human health, but researchers have been isolating these exosomes and investigating whether they can be used as PD biomarkers
• Myocardial Scintigraphy: A specific type of nuclear scan of the heart can demonstrate nerve cell loss in PD and is being investigated as a biomarker for PD.

APDA is aiding the search for a biomarker

Knowing how impactful it will be to find one or more biomarkers, APDA is funding several 2018-2019 researchers who are investigating potential PD biomarkers:

Dr. Daniel Joyce has shown that people with PD have deficits in light sensing pathways critical for controlling sleep, and that these deficits can be detected by assessing the pupil’s response to light.  Dr. Joyce is developing a test of pupillary function to be used as a simple biomarker of PD.

Dr. Yuanfang Guan is working to generate a state-of-the-art algorithm for using voice information generated from mobile devices to predict and follow PD.

Dr. Elizabeth Disbrow previously identified imaging markers on MRI that were associated with the rate of PD progression. She is now investigating differences in these markers of disease severity across racial groups.

Dr. Tim Bartels is studying the properties of lipids, or fat particles, within Lewy bodies, the pathologic hallmark of PD. He is researching whether changes in lipid properties can act as a biomarker of PD.

Tips and takeaways

• A search is underway for a PD biomarker, a measurable characteristic in the body which indicates that disease is present. The biomarker can be a lab test, an imaging test or a clinical test.
• An ideal PD biomarker should be able to detect disease early, quantify disease, distinguish PD from all other conditions, while being affordable, easy to obtain, and reproducible.
• A PD biomarker would help in early diagnosis, accurate diagnosis, disease monitoring and improvement of clinical trials.
• APDA is currently funding several researchers in their search for a PD biomarker.