A Proposed Biological Staging System for Parkinson’s disease

What is a disease staging system?

A disease staging system is a framework used to describe the progression or severity of a particular medical condition. A staging system creates a standardized way of classifying the extent of the disease, which helps healthcare professionals communicate effectively about a patient’s condition, make treatment decisions, and predict prognosis. Many people may be familiar with this regarding diseases like cancer, but there are also staging systems for Parkinson’s disease. We’ll discuss the standard staging scales that have been in use for decades, as well as a newer staging system that is being proposed.

Hoehn and Yahr scale for Parkinson’s stages

The currently used staging system for Parkinson’s disease (PD) is referred to as the Hoehn and Yahr scale, which was developed by Drs. Margaret Hoehn and Melvin Yahr in 1967, and is based on a neurologist’s observation of motor symptoms of the disease. 

Stages of Parkinson’s disease:

• Stage I: Symptoms involve one side of the body
• Stage 2: Symptoms involve both sides of the body, or the midline (that is, symptoms affect structures in the middle of the body such as speech abnormalities)
• Stage 3: Symptoms involve both sides of the body, with impairment of balance
• Stage 4: Symptoms have advanced to the point that although the person can stand and walk without the help of another person, he/she has significant disability. People in this stage typically need at least some help to perform their activities of daily living or self-care activities such as eating, bathing, dressing, and toileting
• Stage 5: The person cannot stand or walk without the help of another person

Limitations of the Hoehn and Yahr scale

The Hoehn and Yahr scale focuses solely on the progression of motor symptoms and does not consider the psychiatric, cognitive, and autonomic non-motor symptoms that often cause more disability than motor symptoms as PD advances. This is a major limitation of the Hoehn and Yahr scale.

In addition, there is no set timeline for how a person progresses through the Hoehn and Yahr stages. For example, many people stay at Stage 2 for a long time, perhaps decades. Many never progress beyond Stage 3. They may develop other health issues as they age that become more prominent than PD. Therefore, the current clinical staging of PD is not that useful for prognostication.

Unified Parkinson Disease Rating Scale

There is another scale that people with PD will be familiar with, the Unified Parkinson Disease Rating Scale (UPDRS). This is a series of brief clinical tests that include the neurologist’s assessment of facial expression, voice, tremor, speed of movement in all four limbs, degree of 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. The UPDRS has been validated and when performed correctly, it is generally reproducible from one clinician to another. However, the UPDRS is not an actual disease staging system since it varies widely based on medication doses and other variables. It is a measure of how a person with PD is doing at a particular moment and is not used for prognosis.

Clinical staging vs biological staging

A major drawback to having a clinical staging system based only on motor symptoms is that it means that the definition of disease starts with motor symptoms. But we know that the pathological disease processes of PD start much before motor symptoms manifest, and they often cause non-motor symptoms first.

Many other diseases, such as cancer, have staging systems rooted in the biology of the disease and not in the clinical features that are observed by a doctor. With the recent advances in various biomarkers for PD, scientists and clinicians have been working on the potential of a biological system for staging PD.

Biological staging is based on the presence of biomarkers

A biomarker is any measurable characteristic in the body that indicates that disease is present. The biomarker can be a lab test, an imaging test, or a clinical test. There are many reasons for finding a PD biomarker, including earlier and more accurate diagnosis. Biological staging of disease requires the identification of one or more biomarkers that can correlate to the presence of the disease. If the biomarker is quantitative, meaning that the amount of the biomarker detected correlates with the degree of disease, then the biomarker could also be used to monitor disease progression and, possibly by extension, prognosis.

Until recently, there were no biomarkers available to detect PD, hence the reliance on the clinical staging and scaling described above. However, the search for biomarkers is now in full swing and some potential biomarkers that have been investigated in the context of PD include:

1. Alpha-synuclein pathology in cerebral spinal fluid: Abnormal accumulation of alpha-synuclein protein in the brain is a hallmark of Parkinson’s disease. Detecting and quantifying alpha-synuclein aggregates could potentially serve as a biological marker. To that end, an assay called seed amplification assay (SAA) is now available as a test on cerebral spinal fluid (CSF).
2. Phosphorylated alpha-synuclein: Research has demonstrated that phosphorylation, or the attachment of a phosphate group, onto the alpha-synuclein molecule can result in a particularly harmful form of alpha-synuclein. Phosphorylated alpha-synuclein can be found in nerves all over the body of a person with PD including in nerve fibers of the skin. These nerves can be accessed for study in a lab via a skin biopsy. Biopsies of other body tissues are under investigation as potential biomarkers as well.
3. DaTscan: A DaTscan, or dopamine transporter scan, is a method of imaging the dopamine system in the brain. In this test, a radioactive tracer, Ioflupane, 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. Several hours after the tracer has been injected, special imaging equipment scans the head to detect the presence of DaTscan. People with PD will typically have a smaller signal in a part of the brain called the striatum, where the ends of the dopamine neurons are meant to be.
4. Genetic mutations: Similar to other complex diseases, whether a person develops PD or not is due to a combination of genetic and environmental risk factors. Genetic mutations that raise the risk of PD are not biomarkers in the traditional sense, since merely having the genetic mutation does not indicate the presence of disease. However, certain genetic risk factors can be taken into consideration when evaluating the diagnosis, progression, and prognosis of the disease.

The scientific community is now evaluating these biomarker elements and efforts are underway to create a biologic staging of PD. For those who are interested in testing for the above-mentioned biomarkers, please consult your neurologist to better understand what options are best for you.

Advancements in biologically defined staging systems

In one biological staging system, presented in this paper, the authors define a new pathologic condition that they name Neuronal synuclein disease (NSD). NSD includes conditions in which both abnormally aggregated alpha-synuclein, detected with an abnormal SAA, and dopaminergic neuron dysfunction/degeneration, detected by an abnormal DaTscan, are present. The rest of the scale, which has not been completely defined yet, is characterized by clinical symptoms. NSD includes REM sleep behavior disorder, PD, and Dementia with Lewy Bodies, as well as asymptomatic people. This proposed staging system therefore moves the diagnosis of PD to much earlier on the disease continuum than when utilizing a strictly clinical scale.

A second system combines pathological alpha-synuclein in tissues such as skin or CSF, evidence of underlying neurodegeneration defined by neuroimaging, and genetic changes that increase the risk of PD to define a staging system. The paper presenting this system (which they name SynNeurGe) is currently in press, so can’t yet be fully evaluated.

One change that will result from biologically defining PD and its related disorders is that it will allow clinical trials to be conducted on people who are much earlier in the disease process. The hope is that intervening in the disease process earlier when less neurological damage has occurred in the brain, will increase the chance that a medication in a clinical trial will be effective.

Challenges in Parkinson’s biological staging

The International Parkinson & Movement Disorders Society (MDS), a society for healthcare professionals who treat PD and related disorders, recently published an article presenting their summary and recommendations on the biological staging of PD. The article outlines various issues that may interfere with the current acceptance of these proposed staging systems. Among these are issues with the SAA biomarker, one of the lynchpins of the biological staging system.

These issues include:

• Currently, SAA results are not quantifiable, meaning that the assay does not measure how much abnormal alpha-synuclein was originally in the brain, and therefore cannot be correlated to the extent of disease.
• If SAA results are positive in the absence of symptoms, the results do not help us predict when a clinical syndrome will develop, which one will develop, or even if one will develop at all. This significantly limits its prognostic ability.
• The test currently requires a CSF sample, which means that to biologically stage a person with PD, a lumbar puncture must be performed, a significant limitation on its practical use.
• SAA, as it is currently performed, is positive in both PD and Multiple system atrophy (MSA) a similar but distinct disorder with a more rapid progression and worse prognosis. Distinguishing between these two disorders is a major current challenge that a new biological staging system should be designed to solve.

For these reasons and others, the MDS suggests that as exciting as moving towards a biological staging system is, much work lies ahead. The staging system must be thoroughly validated before it is accepted across the field of Movement disorders to ensure that it is a useful tool to help healthcare professionals inform their patients about their condition and prognosticate about their future.

Tips and takeaways

• For decades, the staging of PD has been based on clinical observation.
• With the development of new PD biomarkers, scientists are trying to establish a biological staging system for PD.
• The proposed staging system defines a new disease category named Neuronal synuclein disease or NSD.
• NSD includes conditions in which two abnormal biomarkers are present – abnormally aggregated alpha-synuclein, detected with an abnormal seed amplification assay, and dopaminergic neuron dysfunction/degeneration, detected by an abnormal DaTscan.
• The International Parkinson & Movement Disorders Society anticipates and recommends that the staging system be thoroughly validated before it is accepted across the field of Movement disorders to ensure that it is a useful tool for prognostication.
• Biomarker discovery continues to be a critical element of APDA’s research efforts including Dr. Stephan Grimaldi’s search for an MRI-based biomarker and Dr. Xianjun Dong’s search for an RNA biomarker.