Parkinson's Subtypes Predict Prognosis

January 18, 2019

Patients with Parkinson's disease may be stratified on the basis of specific subtypes that progress differently and that are associated with different prognoses, a new study suggests.

"We have found that it is possible to accurately predict prognosis, disability, and survival of patients with Parkinson's disease by classifying them into different clinical subtypes at the time of diagnosis," senior author Thomas Warner, MD, University College London Queen Square Institute of Neurology, United Kingdom, told Medscape Medical News.

"These subtypes may have different underlying problems affecting the nervous system which now need to be identified and which may lead to the development of treatments for specific clinical subtypes," he added.

The study was published online in JAMA Neurology on January 14.

The researchers used life course clinical information from 111 Parkinson's patients who had donated their brains to research after death.

They developed a classification system that is based on the severity of the cardinal movement problems in Parkinson's and key nonmotor symptoms, including cognitive function, autonomic symptoms (control of blood pressure, urinary function), and REM (rapid eye movement) sleep behavior disorder according to the clinical impression of the treating physicians.

"Together with the classical motor features, a simple assessment of relevant nonmotor symptoms can now allow clinicians to provide an accurate estimation of the disease course at the time of diagnosis, allowing better counseling, management of symptoms, and planning care of potential complications," Warner said.

Three main subtypes have been proposed:

  1. Mild-motor predominant: Motor and all nonmotor scores less than the 75th percentile

  2. Diffuse malignant: Either motor score greater than the 75th percentile and at least one nonmotor score greater than the 75th percentile or all three nonmotor scores greater than the 75th percentile

  3. Intermediate: All those individuals not meeting criteria for other subtypes

Warner explained that in the mild-motor predominant category, patients present with mainly movement problems. It is associated with the best prognosis and survival. In the diffuse malignant subtype, patients have a combination of motor and nonmotor symptoms on presentation. This subtype represents a more aggressive and progressive clinical picture. The intermediate group has an intermediate prognosis.

He noted that the neurology community has always recognized that patients who present with prominent tremor often have a better prognosis. "These would now be considered as the mild motor predominant group," he said.

In the current study, 48.7% of patients were categorized as having the mild-motor predominant subtype, 35.1% as having the intermediate subtype, and 16.2% as having the diffuse malignant subtype.

Patients with the mild-motor predominant subtype were significantly younger at diagnosis, responded better to levodopa, and received a higher levodopa equivalent dose. Patients with the diffuse-malignant subtype were older, were almost all men, responded more poorly to levodopa, and were more frequently misdiagnosed as having an atypical parkinsonian syndrome in life.

Patients with the diffuse malignant subtype reached all prognostic milestones earlier in the disease course (hazard ratio, 10.90; P < .001) and had the shortest survival from diagnosis (8.1 years vs 15.8 years for the mild-motor predominant group).

Staging of Lewy pathology and Alzheimer disease–related pathology did not differ between subtypes, although these factors were associated with different rates of progression, and the latter was associated with age at death.

Warner explained that in the mild-motor predominant category, patients present with mainly movement problems. It is associated with the best prognosis and survival. In the diffuse malignant subtype, patients have a combination of motor and nonmotor symptoms on presentation. This subtype represents a more aggressive and progressive clinical picture. The intermediate group has an intermediate prognosis.

"Our findings confirm that these subtypes are a reasonable way of classifying patients, add much needed prognostic information, as we have data on the whole disease course and pathology, and we have simplified the information needed at diagnosis to make the classification easier to implement in the clinic," Warner said.

Their study took into consideration the whole life course of Parkinson's in cases definitively diagnosed by neuropathologic study of the brain, he added. "In life, there is a level of diagnostic error of clinical diagnoses, as other conditions can mimic Parkinson's. It is important to have data over the whole duration of the disease, including pathology information, to accurately define the subtypes and their prognosis."

He also pointed out the importance of nonmotor symptoms in the diagnosis. "We have shown that the nonmotor features are not just contributors to the clinical burden, but they are also negative prognostic markers, and their evaluation should be part of every routine clinical assessment."

Warner concluded, "Our results support the idea that different mechanisms and/or modifying factors may drive the clinical heterogeneity in Parkinson's subgroups, including the variable response to available medications seen in our study. It seems that differences in the progression of Lewy pathology and other neuropathologic changes (Alzheimer's disease pathology) are one of the factors contributing to the variability of Parkinson's disease."

Better understanding of these and other factors will "open up the avenue for more effective individualized treatments based on the underlying pathophysiological mechanisms," he said. "Until target treatments become available, Parkinson's clinical subtyping, including nonmotor features, should be incorporated in clinical research, and the assessment of any future drugs in clinical trials should be stratified by Parkinson's subtypes which may help with the understanding of Parkinson's pathophysiology."

The research was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Center. Dr Warner receives research support from the Reta Lila Weston Medical Trust, the Brain Research Trust, Cure Huntington's Disease Initiative, the Medical Research Council, and Corticobasal Degeneration Solutions. The other authors' relevant financial relationships are listed in the original article.

JAMA Neurology. Published online January 14, 2019. Abstract

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