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Parkinson’s Disease Subtypes: Critical Appraisal and Recommendations

Background: In Parkinson’s disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice. Objective: To critically evaluate PD subtyping systems. Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists. Results: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown. Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.

of study design, and both clinical and non-clinical biomarkers as measures. We only included fulltext publications written in English. We excluded studies or results within a study which compared PD with healthy controls or other neurological disorders, studies evaluating previously-defined PD subtypes (i.e., tremor dominant vs. PIGD) or using a mixed group of patients as unit of analyses, biomarker studies with no categorical results (no sub-grouping of patients based on the biomarker), studies restricted to a subset of PD patients (e.g., cognitively impaired) and review articles.

Search strategy
We searched for PD subtyping studies in the medical databases PUBMED/MEDLINE and Three expert reviewers (SMF, TAM, CM) were responsible for the initial screening of each abstract identified through the search. Any disagreements regarding abstract inclusion between the two reviewers were discussed with and assessed by the third reviewer for a final decision. Each full-text article of abstracts remaining after the initial screen was reviewed by at least two members of the MDS Task Force, who made final decisions regarding inclusion of the paper and performed data collection.

Data collection
Pairs of reviewers abstracted data from the original studies regarding study design, baseline characteristics, PD subtyping methodology and results were entered into a standardized data sheet.
Reviewers could not evaluate their own studies.

Rating schemes
In the absence of available tools to specifically evaluate subtyping studies, we developed our own checklists to assess the methodological quality and clinical applicability of the included studies. The Methodological Quality tool is a 13-item checklist with item scores ranging from 0 to 2. A higher score corresponds to higher methodological quality. The Clinical Applicability tool is an 11-item checklist with items rated as Unknown, Limited/Low, Moderate, and Strong. We drafted an initial version based on available standardized checklists [1]. After reaching a consensus across the Task Force in terms of items and response options, we tested the application of both tools in a sample of included studies (N=5) to refine the tools and finalize the version used in this review. An item on appraisal of statistical methods was included in the Methodological Quality tool. Due to the heterogeneity of the statistical methods used, a pair of statisticians (MM, ML) was given the task of reaching a consensus on rating criteria for this item based on pre-defined statistical evaluative concepts. The same pair of statisticians obtained a final score (0=low quality, 1=intermediate quality, 2=high quality) by consensus, taking into account all aspects of the study and incorporating discussion to arrive at agreement, recording reasons for sub-optimal ratings. For both study data collection and rating schemes, reviewers were requested to extract data and rate the studies independently. Discrepancies were subsequently resolved by consensus between the raters within a pair.

Data analysis
We provide descriptive statistics of the data abstracted and ratings of the Methodological Quality and Clinical Applicability tools. We used chi-square tests (or Fisher's exact test, as appropriate) to compare the relative frequencies of ratings by individual items between two publication periods (1980-2014 vs. 2015-2019) as well as between two methodological approaches (data-driven vs. hypothesis-driven).