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3 Different Clinical Subtypes of Parkinson's Disease, 3 Different Course of Progression

Article In Brief


Factors contributing to neuropathologic heterogeneity in PD: Lewy pathology seems directly associated with the duration of the disease in a proportion of patients with slow clinical and pathologic progression. Distribution of Lewy pathology is also variable, and at least a proportion of those patients presenting with early dementia show diffuse neocortical Lewy pathology since the onset compared with the typical caudo-rostral pattern of progression seen in most patients. Particularly important in elderly patients is the presence of Alzheimers disease pathology, which is directly associated with age at death.

Based on a review of the medical records of patients with Parkinson's disease (PD) from the time of diagnosis through their death and post-mortem pathology, researchers characterized three different PD clinical subtypes. The subtypes could be useful prognostic tools for predicting disease progression, the study authors say.

British scientists have identified three distinct clinical subtypes of Parkinson's disease (PD) that could offer insights into the disease's progression over time.

Neurologists have attempted to come up with a classification system based on the severity of motor symptoms, sleep problems, and autonomic and cognitive function at diagnosis. There are a handful of new classification systems but few neurologists rely on them to help inform the progression of the disease, experts told Neurology Today. Now, a new study pulled together retrospective data from the medical records of patients with PD and their post-mortem pathology reports to identify outcomes associated with three different clinical subtypes of disease.

Identifying the disease subtype could offer prognostic clues about how the disease would progress, offering patients valuable insights into their condition, suggests the study published in the January 14 online edition of JAMA Neurology.

Study Design

The lead study author, Eduardo De Pablo-Fernandez, MD, a clinical research fellow at University College London (UCL), and colleagues decided to design a study to evaluate and subtype patients by looking at their medical records at the time of diagnosis. They used a classification system put together by researchers at the Montreal Neurological Institute, which looks at how the condition progressed from the time of diagnosis until death.

Based on the classification system, the patients were separated into one of three subtypes: mild-motor predominant, intermediate, or diffuse malignant. [For more on the classification system, see “Three Clinical Subtypes of Parkinson's Disease.”]

“We can see by looking back at the first signs of symptoms that the subtypes do predict how the disease will progress,” said Dr. De Pablo-Fernandez, whose mentor and senior study author is Thomas T. Warner, MD, PhD, director of the Reta Lila Weston Institute at UCL Institute of Neurology. “This analysis suggests that we may be able to use this type of classification to help guide treatment, as well as help patients better understand their disease course.”

Those who had a diffuse malignant subtype were older, experienced faster disease progression, and were less responsive to medication, he explained. They also did not live as long as those classified with a mild subtype who were younger at diagnosis, had less severe motor symptoms and minimal distress, and often did not need medication until later. The intermediate subtype included patients who fell in between the two groups and who responded to therapy.

Study Design, Findings

Patients in the study had agreed to donate their brain at death to the Queen Square Brain Bank. Each of them had been seen from the time of diagnosis through to death by hospital specialists in the United Kingdom who had access to the patients' detailed medical records.

The UCL team analyzed the medical records from 111 patients whose brains arrived at the brain bank between 2009 and 2017. They used the earliest records to identify the symptoms at the time of diagnosis. Neurologists reviewed the records and subtyped each patient based on the severity of motor symptoms, rapid eye movement sleep behavior disorder, and autonomic and cognitive function at diagnosis. They were classified as either mild-motor predominant, intermediate, or diffuse malignant subtypes.

They looked at the time from diagnosis to death and measured disability with disease milestones, including falls, dependence on a wheelchair, dementia and whether they had to be placed in a nursing home, and if so, when. They looked to see whether the subtypes at diagnosis were strong enough to predict how their lives would fare post-diagnosis.

People in the mild-motor predominant group were diagnosed on average in their mid-50s and had a slower course. Those with the most severe subtype—diffuse malignant—were diagnosed later in life (70.3 years) and reached their PD milestones faster, including complications such as dementia.

The scientists wanted to assess any pathological changes that may have related to cognitive impairment in PD. But while the subtypes showed different rates of clinical progression, they found no difference in the Lewy body and Alzheimer's disease pathology in autopsied tissue. The neuropathologists were blinded to the patient's symptoms and disease course.

“Patients in these subgroups are very different,” said Dr. De Pablo-Fernandez. The neurologists who blindly assessed the medical records and subtyped the patients were accurate in their predictions of how the disease progressed, he said, adding that the classification would also be helpful in PD clinical trials to evaluate treatments that may be beneficial to specific subgroups of patients.

“One of the first questions patients ask is, ‘What is going to happen to me?’” Dr. De Pablo-Fernandez said. “These tools would be helpful in clinical practice to guide patients on what is going to happen so that they can plan for their future.”

Expert Commentary

“Parkinson's disease subtyping currently is not widely used to stratify patients and their disease prognosis due to lack of data and clinical consensus,” said Nikolaus McFarland, MD, PhD, assistant professor of neurology and chief of the movement disorders division at University of Florida College of Medicine in Gainesville. “Tremor-predominant and postural instability-gait difficulty subtypes have been proposed but these are based primarily on motor phenotypes.”

“The current study is significant as the authors used both motor and non-motor features of PD, including REM sleep behavior, dysautonomia, and cognitive dysfunction,” Dr. McFarland said. “Further, diagnosis of PD in the cohort studied was confirmed by autopsy. The study demonstrates compelling evidence that subtyping PD at the time of diagnosis into three categories—mild-motor predominant, intermediate, and diffuse malignant—may provide an accurate estimate of future disease course and survival. A further intriguing finding is that the neuropathology at autopsy appeared similar for each disease subtype, suggesting earlier or more rapid or widespread progression of neuropathology in intermediate and diffuse malignant PD subtypes.”

But he offered these caveats in his review of the study: the study conclusions could have been limited by the retrospective nature of the study, the relatively small sample size, and the advanced pathologic stage of the patients, Dr. McFarland said.


“This analysis suggests that we may be able to use this type of classification to help guide treatment, as well as help patients better understand their disease course.”—DR. EDUARDO DE PABLO-FERNANDEZ

“Although the findings of this study are significant and compelling, further evidence and validation of the proposed PD subtypes is needed before adopting them in practice,” he said. “Clinicians should use the information regarding PD subtypes cautiously to guide discussions regarding prognosis.”

“From a clinical standpoint, there are people who have milder symptoms and others who degenerate quickly,” said David Eidelberg, MD, director of the Center for Neuroscience at the Feinstein Institute for Medical Research, part of the Northwell Health System in Manhasset, NY.

“It makes sense to treat the clinical data as symptom clusters, which can be correlated with the post-mortem assessments. Indeed, the results accord well with the existence of discrete clinical subtypes of PD with mild and more aggressive disease progression,” Dr. Eidelberg said. “Prospective validation studies are needed to determine the impact of baseline subtype on the subsequent motor deterioration that occurs in individual patients.”

3 Clinical Subtypes of Parkinson's Disease

Investigators applied criteria assessing severity scores of motor and nonmotor features of the disease, and converted them into four domains that included one composite score for motor (comprising scores for tremor, bradykinesia, rigidity, and postural instability); one composite for autonomic dysfunction (comprising scores for urinary symptoms, constipation, symptoms of upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, and erectile dysfunction in men), and two individual scores for REM behavior disorder and cognitive dysfunction.

They calculated the corresponding 75th percentile for each domain and used that as the basis for classifying patients at the time of diagnosis into the three subtypes:

  • Mild-Motor Predominant: motor and all nonmotor scores less than the 75th percentile.
  • Diffuse Malignant: either motor scores greater than the 75th percentile and at least one nonmotor score greater than the 75th percentile or all three nonmotor scores greater than the percentile.
  • Intermediate: individuals who did not meet criteria for other subtypes.

Link Up for More Information

• De Pablo-Fernandez E, Lees AJ, Holton JL, Warner TT. Prognosis and neuropathologic correlation of clinical subtypes of Parkinson disease JAMA Neurol 2019; Epub 2019 Jan 14.