Proposed Parkinson’s Subtypes May Best Capture Disease Stages

A proposed system for classifying subtypes of Parkinson’s disease is strongly linked to disease duration and severity, a new study found. This suggests that the system’s proposed subtypes might actually reflect different stages of the disease, rather than distinct clinical subtypes.

The study, “The role of disease duration and severity on novel clinical subtypes of Parkinson disease,” was published in Parkinsonism & Related Disorders.

Parkinson’s progression, as well as its clinical manifestations, varies across patients, suggesting distinct disease subtypes might exist.

Finding different subtypes of Parkinson’s has long been a research goal, as this could allow for more individualized treatment approaches. However, classifying patients into distinct groups that are clinically or biologically meaningful over time has proven a challenge.

A few years  back, a framework was proposed that divides Parkinson’s into three subtypes: mild motor-predominant (MM), diffuse-malignant (DM), and intermediate. These divisions are based on symptoms experienced, particularly motor symptoms, cognitive impairment, rapid eye movement (REM) sleep disorder, and dysautonomia (abnormalities in the autonomic nervous system, which controls involuntary bodily processes like heart rate and sweating).

However, other research has suggested that these subtypes might reflect different stages of the same disease over time, rather than distinct clinical subtypes. The basic idea is that someone early into the disease, and experiencing more mild symptoms, might be classified as mild-motor predominant. But later,  as the disease progresses and symptoms worsen, this same person could be classified as intermediate or diffuse-malignant.

In this study, researchers “aimed to test the influence of disease duration and stage on these novel clinical subtypes” in a group of people with Parkinson’s.

A total of 122 patients (82 males, 40 females; average age, 66.17 ; average disease duration, 5.85 years) were classified according to this system: 49 (40.16%) were included in the mild-motor predominant subtype, 29 (23.78%) in the diffuse-malignant subtype, and 44 (36.06%) in the intermediate subtype.

The researchers compared disease duration — that is, the amount of time since symptoms started — among the three groups. On average, the shortest disease duration was found for the mild-motor predominant subtype (3.75 years), and the longest for the diffuse-malignant subtype (11.04 years), with the intermediate subtype in between (5.11 years).

Subtypes were also examined based on disease duration. Among those with a disease duration of less than five years, 58.34% were classified as mild-motor predominant, compared to 22.58% for those diagnosed 10 or more years ago. For diffuse-malignant, the opposite trend was observed: 5% with a disease duration of less than five years, and 51.61% for 10 years or more.

These subtypes were also associated with those of the Hoehn and Yahr scale (H&Y), which measures disease progression in stages based on severity of symptoms. Broadly, people classified in an earlier stage of disease by H&Y were more likely to be mild-motor predominant than were those classified as having more advanced disease. The opposite was again observed for diffuse-malignant (later stage by H&Y), with the intermediate subtype lying between the two extremes.

Collectively, these data show that the mild-motor predominant, diffuse-malignant, and intermediate subtypes are closely associated with disease duration and stage. This supports the idea that these divisions may actually represent changes in the disease over time, rather than variations person-to-person.

But, the researchers stressed, these findings don’t mean that the subtyping system is wrong, just that its implications need clarification.

“Our results are not in contrast with previous evidence and do not aim to challenge this subtyping system as such, but would call for a clarification of what the construct of subtype should mean,” the researchers wrote.

“Since a patient with MM phenotype at onset will be likely to convert into the DM phenotype at some point, the implication is made that a particular subtype is not able to predict if certain milestones will be reached or not,” they added. “On the other hand, the current data also shows that a proportion of patients have reached the DM stage with short disease duration, which supports the notion that a difference in the rate of progression exists among PD patients.”

The current study’s findings “argue against the concept that these subtypes reflect mutually exclusive disease pathways,” the researchers continued. “The evidence that these subtypes might be not consistent over time has to be taken into account, specifically when attempting to explore correlations with putative biomarkers of disease progression.”

An important caveat of this study is that it was cross-sectional — that is, data were collected at a single point in time, and findings were extrapolated from those data. Further longitudinal studies, which collect data over a length of time, will be needed to validate these findings.