Parkinson’s Subtypes: Heterogeneity, Prognosis, and Treatment Development

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Each person's experience living with Parkinson's is different. In addition to differences related to personal circumstances and living situations, no two people will have the same motor symptoms, non-motor symptoms, or rate of progression.   

The differences in how people experience Parkinson's symptoms are sometimes referred to as phenotypes. Due to the diverse phenotypes of Parkinson's, many people, including researchers and movement disorder specialists, consider Parkinson's to be more than one disease.  

Parkinson's Subtypes  

For many years, Parkinson's specialists have grouped similar Parkinson's phenotypes into Parkinson's subtypes. Six of the most common ways to subtype Parkinson's are to differentiate—  

  1. Between Parkinson's and other types of Parkinsonism  
  2. By the age of onset  
  3. As genetic/familial or idiopathic  
  4. By which symptoms are most prominent  
  5. By whether a person's Parkinson's began in the gut or the brain  
  6. By severity and variety of symptoms  

Complications with Subtyping  

The current understanding of Parkinson's subtypes is not perfect, and more research is needed to confirm the validity of Parkinson's subtypes and identify their underlying biological mechanisms.  

One example of an imperfect understanding of subtypes is that studies involving symptom-based subtypes have found that a person's subtype can be different when they are ON than when they are OFF. Other studies have shown that even among people who do not shift subtypes when they are ON or OFF medication, a person's Parkinson's subtype can change in less than two years.  

Why Subtypes Matter  

Establishing and confirming the validity of Parkinson's subtypes is important because understanding them may impact a person's decisions about their treatment and approach to living well. Moreover, having validated subtypes—subtypes that have been identified and clinically confirmed—will also improve the quality of research.  

For example, improving our understanding of Parkinson's subtypes will help expedite the drug development process by ensuring that the people most likely to benefit from any particular treatment are well-represented in the clinical trial. This already happens in some trials, such as gene therapy trials, where genetic status is among the inclusion criteria. Other subtype classifications, such as the age of onset and the symptoms that a person experiences, are also sometimes used to group clinical trial participants.  

Another important consideration is that effective subtyping of Parkinson's will influence and be influenced by the search for Parkinson's biomarkers. Finding verifiable biomarkers is critical to advancing research to cure Parkinson's. Still, some Parkinson's specialists think that if Parkinson's is not just one condition, every person with Parkinson's may not present the same biomarkers.   

Distinctions and Complications of Current Common Subtypes  

Even while our understanding of subtypes is not perfect, understanding your Parkinson's subtypes can provide valuable information to help you live well today.  

Parkinson's and Other Parkinsonism  

Differentiating between types of Parkinsonism was one of the first ways to subtype Parkinson's. There are many types of Parkinsonism, and some of the more common types are discussed in this post 

One important distinction between Parkinson's and other Parkinsonism is that some types of atypical Parkinsonism respond less well to levodopa. Another difference between Parkinson's and atypical Parkinsonism is that progression of some atypical Parkinsonism tends to be faster than the progression of Parkinson's. There are also differences in the parts of the brain affected and the types of symptoms a person is likely to experience. These differences may influence treatment decisions and plans for the future.  

Age of Onset  

Age of onset is another long-standing way to subtype Parkinson's. This subtyping is also helpful in considering treatment options and timing.  

For example, the American Academy of Neurology (AAN) notes in their 2021 treatment guidelines that people with a younger Parkinson's onset may benefit from initial treatment with dopamine agonists rather than levodopa. However, age of onset is not the only factor in this decision. The AAN treatment guidelines also note that dopamine agonists correlate with a higher incidence of impulse control disorders, including for younger males and those with a history of mood disorders.   

Age of onset has also been associated with a higher likelihood of having a genetic cause of Parkinson's and a pattern of early symptoms, including rigidity, cramping, and dystonia. Moreover, people with a younger onset tend to have a lower incidence of cognitive impairment, a slower rate of progression, and a milder symptomatic experience of Parkinson's.   

Importantly, these associations are not indicative of every person's experience, and the rigidity experienced by some people living with young onset Parkinson's can contribute to pain and falls, which can significantly affect quality of life.  

Genetic Subtypes  

There is a lot of research investigating genetic subtypes of Parkinson's. One reason for this is that understanding what genes are involved in an individual's experience of Parkinson's can help focus efforts to develop new treatments.   

One example of targeted new treatments relates to mutations/variants in the GBA gene. GBA variations often result in altered levels of the GCase protein, and multiple ongoing clinical trials aim to normalize GCase levels. Examples include gene therapy trials and pharmaceutical interventions like ambroxol. Someone with a GBA mutation who has Parkinson's may be a good candidate to participate in these trials.   

Importantly, treatments that focus on gene function could be beneficial for all people with Parkinson's, not just those with genetic variants; however, starting research by involving people with Parkinson's who are most likely to respond to a particular treatment can optimize early-stage research.  

Symptom Prominence  

One of the more complicated ways to subtype Parkinson's is by the most prominent symptoms a person experiences.   

One complication of subtyping this way is that there is often variation between individuals in these groups. For example, the age of onset and level of activity before diagnosis influence symptom severity and other aspects of quality of life. Another example is that variations in non-motor symptoms are common even among people with similar motor symptoms.   

Another complication is that, unlike in the case of a genetic mutation, where there are often known biological markers that correlate with the subtype, biomarkers for most symptoms need to be better understood.  

Examples of symptom-prominence subtypes include—  

Tremor Predominant  

This subtype is characterized by tremor as the most prominent symptom, with little or no impairment in balance or gait. People living with this subtype may have a slower progression and a better prognosis than other subtypes. This is partly because the typical Parkinson's resting tremor tends to interfere less with general mobility than bradykinesia-predominant Parkinson's.  

Bradykinesia Predominant  

Bradykinesia-predominant Parkinson's is characterized by slow movement and difficulty initiating or completing actions like taking a step or reaching for an object. For example, bradykinesia-predominant Parkinson's increases the likelihood of falls.   

People with bradykinesia-predominant Parkinson's often experience only a mild or inconsistent resting tremor, but they tend to experience a higher incidence of action or postural tremors.   

A 2022 study found that many people who experience significant bradykinesia—especially in the morning—are at an increased risk of being undermedicated throughout the day. One possible reason for this is that bradykinesia is typically less noticeable when a person isn't active, so a person with bradykinesia-predominant Parkinson's might not always recognize the intensity of their symptoms.   

Because of the risk of under medication and the increased likelihood of falls, it is essential for people with bradykinesia-predominant Parkinson's to carefully monitor their symptoms throughout the day and follow the schedule for their medications that they establish with their care team.   

Postural Instability and Gait Difficulty (PIGD)   

This subtype is characterized by having difficulties with balance, posture, and walking, often with mild or absent tremor. People living with this subtype tend to have a faster and more severe progression of symptoms, an increased likelihood of falls, and a greater likelihood of cognitive impairment and dementia.  

A 2022 study of 292 people with Parkinson's found that PIGD Parkinson's was also correlated with higher rates of autonomic symptoms, including gastrointestinal issues, difficulties with heat regulation, and interrupted sleep. The study's authors observe that the PIGD subtype could relate to sleep disruptions. They note that early identification of the PIGD subtype may help improve quality of life by treating sleep and gastrointestinal issues earlier.  

REM Sleep Behavior Disorder (RBD)   

RBD is a condition where people act out their dreams and move significantly while they sleep. For some people, this is the earliest prominent symptom of Parkinson's. The RBD subtype is an example of a prodromal subtype 

A 2017 study found that people with Parkinson's who experience RBD are more likely to experience autonomic dysfunction, olfactory loss, and depression. The study also found that people living with RBD Parkinson's are nearly three times more likely to experience mild cognitive impairment than people who do not experience RBD.  

Body-First or Brain-First  

The body-first/brain-first subtyping attempts to avoid some of the challenges of changing motor subtypes and heterogeneity within subtypes. Body-first Parkinson's starts with motor symptoms, such as tremor, rigidity, slowness of movement, balance problems, and gait disturbances. Brain-first Parkinson's starts with cognitive and behavioral symptoms, such as depression, anxiety, hallucinations, and cognitive impairment, like confusion or trouble with memory.   

The underlying physiological difference between these two types of Parkinson's is thought to be related to the pattern of brain cell loss and the accumulation of abnormal protein deposits. In body-first Parkinson's, the deposits are more concentrated in the brain regions involved in movement control. In brain-first Parkinson's, these deposits are more widespread in the brain regions involved in cognition and emotion. In his 2019 journal article on body-first/brain-first subtypes, one researcher describes these two types: "In the first type, you have quite dramatic damage to the peripheral nervous system, the sympathetic and the cholinergic system, but a normal dopamine system. In the second type, you see a normal peripheral autonomic system, but quite severe damage to the dopamine system in the brain."   

Notably, this subtyping has been debated amongst specialists, with some questioning its practical utility. Other specialists observe that this subtyping could relate to research into the microbiome's role in Parkinson's and could help you and your care team decide whether to pursue interventions that target the gut.   

Symptom Severity  

In an article published in February 2023, researchers describe subtyping Parkinson's using symptom severity. This subtyping method aims to avoid some of the complexities of other subtyping.  

The article describes the use of multiple Parkinson's symptoms to differentiate between three subtypes: mild-motor predominant, intermediate, and diffuse-malignant. The symptoms used to assign subtypes included motor impairment, cognitive function, RBD, and autonomic symptoms.   

The authors of the article write that "neuroimaging studies…show that the diffuse-malignant subtype is associated with heightened excitability and decreased plasticity in the primary motor cortex, disrupted structural connectivity patterns, reduced basal ganglia tissue integrity, more extensive structural atrophy, and greater dopamine loss." The authors go on to observe that the study's findings suggest that mild-motor, intermediate, and diffuse-malignant have different susceptibility to neurodegenerative processes. They write that "the mild-motor predominant subtype resembles…a brain-first type of α-synucleinopathy, which has been associated with relatively benign and focal motor symptoms. In contrast, the diffuse-malignant subtype resembles a body-first type of α-synucleinopathy that is characterized by diffuse motor and non-motor symptoms in combination with a more aggressive disease course."  

The authors also observe that these differences may help discover biomarkers for Parkinson's progression. However, they also acknowledge that a confounding aspect of their study is that nearly 40% of the participants in the two-year study converted from one subtype to another: 25% of study participants converted to a more severe subtype, while 14% converted to a more benign subtype.  

How Does This Affect You Today?  

Even though your subtype today may not be your subtype tomorrow, understanding Parkinson's subtypes can help you and your care team evaluate plans for the future, consider treatment options, and determine what clinical trials could be a good fit for you.  

Moreover, while your subtype may change, which can be challenging and scary, it can also be a source of hope. For one thing, that your subtype of Parkinson's can change means that the most challenging thing you face today might be easier tomorrow. Additionally, although we do not entirely understand why or how subtypes change, we do know that research has shown that people can move from a more malignant and diffuse subtype to a milder subtype. Because we know that exercise can improve Parkinson's symptoms, this may be another reason to find ways to increase your activity today.  

Subtypes offer another source of hope: that researchers are using subtypes to increase understanding of Parkinson's and focus their efforts on more personalized treatments is a positive step toward improving treatments and finding a cure—or cures—for Parkinson's.  

Further Reading  

Research Report Card  

Comprehensive subtyping of Parkinson's  

Multimodal phenotypic axes of Parkinson's  

Brain-first versus body-first Parkinson's  

Commentary on Body-first versus brain-first biological subtyping of Parkinson's  

Clinical classification systems and long-term outcome in mid- and late-stage Parkinson's  

Clinical Subtypes: Key Features & Clinical milestones 


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