An international working group says it is time to re-evaluate the current subtype Parkinson’s disease (PD), which he says has dubious clinical applicability and biological relevance.
The analysis of the studies underlying the current PD subtype has multiple limitations, including the lack of longitudinal data.
“Most of the studies were, for example, cross-sectional,” said study author and working group member Tiago A. Mestre, MD, PhD, associate professor of neurology at the University of Ottawa, Ontario , Canada. Medscape Medical News.
He also noted that the vast majority of studies focused on clinical biomarkers rather than targets.
The researchers noted that future research on PD subtypes should use longitudinal data and include participants whose cases had the same duration of the predefined disease.
The conclusions were published online April 13 a Parkinson’s Disease Journal.
The international working group is investigating
PD is characterized by clinical and pathological heterogeneity. Previously, researchers have attempted to identify subtypes of the disease to understand its heterogeneity, clarify its pathophysiology, and develop better and more specific treatments. It is unclear to what extent research on disease subtypes has achieved these goals.
The International Parkinson’s Disease and Movement Disorder Society established the working group for Parkinson’s disease subtypes in 2018. The goals of the working group were to evaluate the subtype studies conducted so far and indicate areas for future studies in this field.
For the analysis, the working group sought PubMed and MEDLINE to identify studies on PD subtypes. A standardized approach was used to assess the methodological quality and clinical applicability of each study.
The researchers classified the studies included into two groups according to the date of publication. One group included studies from 1980 to 2014 and the other included studies from 2015 to 2019. They compared the average methodological quality of the studies during these two periods.
In total, 38 studies were included in the analysis. Twenty-six (68.4%) were transversal and 32 (84.2%) were performed in tertiary care centers. The average duration of the disease was approximately 60 months. A significant number of studies did not report common patient descriptors, such as unified Parkinson’s disease score scale scores.
Approximately two-thirds of the studies used a data-based approach for subtyping; 21% used a hypothesis-based approach. Most (64%) of the data-based studies identified subtypes using at least three phenotypic domains; 7 of 8 hypothesis-based studies used only one domain.
The motor domain was used most frequently in both types of study, followed by non-motor domains, such as cognitive, emotional, or autonomous domains. Only five studies, all based on data, used nonclinical biomarkers.
Most studies did not achieve high scores on a methodological quality checklist. Weaknesses included recruiting patients from clinics rather than the community, lack of justification for sample size, and failure to match baseline characteristics.
The four highest quality studies were published after 2016. They were longitudinal, data-based studies conducted at various centers. Two of these studies included patients whose cases were of the same stage or duration of the disease. Although these studies incorporated similar clinical domains into their analyzes, there were no clear similarities between the subtypes identified by these studies.
The clinical significance of differences between subtypes was assessed as poor for most studies. The same was true of the possible implications and applicability of the treatment of most studies to the wider population of PD patients. Due to the small number of longitudinal studies, the stability of subtypes over time was unclear, as was their prognostic value.
“Mandatory” biomarker target
Although non-clinical biomarkers are desirable, they are not easy to obtain. “The field of biomarkers has been expanding and I think it is not yet mature, for the most part, in terms of having valid biomarkers that we can use consistently in Parkinson’s disease,” Mestre said. “It’s a need we established after reviewing the available data.”
Two possible goals of subtyping patients with PD are to establish a prognosis and choose treatment.
“If we consider that, any classification we have of the subtypes of Parkinson’s disease will have to be easily applied to clinical practice. I think that was our main consideration to really evaluate the clinical applicability,” he said. Master.
The results suggest several areas for future research on possible PD subtypes. For example, the inclusion of non-clinical domains in the definition of PD subtypes would offer “a way to recognize the biological foundations that would allow us to identify more valid subtypes of Parkinson’s disease,” he added.
Similarly, there is a need for longitudinal studies, which clarify the prognostic relevance of subtypes. Neurologists also need methods to translate group-level data into information relevant to individual patients.
Valuable contribution
Commenting on the research of Medscape Medical News, Raul Martínez Fernández, MD, PhD, neurologist and clinical researcher at HM Puerta del Sur University Hospital in Madrid, Spain, said the study makes a valuable contribution.
“The main strengths of the study are its methodological accuracy and the fact that it addresses an issue that has important clinical and research implications in the field,” he said.
The main weakness of the study is the heterogeneity of the results it analyzed, he added. There are few suitable studies available in the literature and most of them differ in important ways in methodology. This points to the need for greater methodological homogeneity in this research, said Martínez Fernández.
The predominance of cross-sectional studies over longitudinal studies is likely to result from the fact that a cross-sectional study design is less demanding and cheaper, and that these studies can be executed more quickly than longitudinal studies, he noted.
It was important for future research to follow patients before the disease and for a longer period, he added. In addition to clinical presentation and evolution, objective biological markers are needed to define PD subtypes. These markers may include functional neuroimaging studies, cerebrospinal fluid analysis, and genetic testing.
The authors are right to point to the need to establish formal guidelines to focus research in this field, Martinez Fernandez said.
“It is mandatory to define prodromal populations using objective biomarkers and determine measures to objectively assess disease progression,” he added. “Specifically, image markers and neurodegeneration of alpha-synuclein tracers would be essential to understand the progression of Parkinson’s disease, both in general terms and for each subtype.”
The study was funded by the International Parkinson and Movement Disorder Society. Mestre and Martínez Fernández have not revealed any relevant financial relationship.
J Parkinsons Dis. Published online April 13, 2021. Full text
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