Prodromal Markers in Parkinson’s Disease: Limitations in Longitudinal Studies and Lessons Learned

Sebastian Heinzel,Stefanie Lerche,Yoav Ben-Shlomo,Walter Maetzler,Uwe Walter,Marcello Moccia,Daniela Berg,Meike Kasten,Brit Mollenhauer,Richard Dodel,Ulrike Suenkel,Paolo Barone,Henk W Berendse,Stefanie Behnke,Guido Alves,Bastiaan R Bloem,Rejko Krüger,Donald G Grosset,Karin Wirdefeldt,Inga Liepelt‐Scarfone ,David J Burn ,Benjamin Röeben ,Michele T.m Hu ,Wolfgang H Oertel

doi:10.3389/fnagi.2016.00147

Abstract

A growing body of evidence supports a prodromal neurodegenerative process preceding the clinical onset of Parkinson’s disease (PD). Studies have identified several different prodromal markers that may have the potential to predict the conversion from healthy to clinical PD but use considerably different approaches. We systematically reviewed 35 longitudinal studies reporting prodromal PD features and evaluated the methodological quality across 10 different predefined domains. We found limitations in the following domains: PD diagnosis (57% of studies), prodromal marker assessments (51%), temporal information on prodromal markers or PD diagnosis (34%), generalizability of results (17%), statistical methods (accounting for at least age as confounder; 17%), study design (14%), and sample size (9%). However, no limitations regarding drop-out (or bias investigation), or report of inclusion/exclusion criteria or prodromal marker associations were revealed. Lessons learned from these limitations and additional aspects of current prodromal marker studies in PD are discussed to provide a basis for the evaluation of findings and the improvement of future research in prodromal PD. The observed heterogeneity of studies, limitations and analyses might be addressed in future longitudinal studies using a, yet to be established, modular minimal set of assessments improving comparability of findings and enabling data sharing and combined analyses across studies.

Highlights

While numerous longitudinal cohort studies support the concept of prodromal Parkinson’s disease (PD) and prodromal markers (e.g., Abbott et al, 2001; Postuma et al, 2015; Schrag et al, 2015), the comparability of study results is hampered by methodological differences (Lerche et al, 2015), such as design, type of assessments and analytical methods
We indicated whether studies were population-based or clinical cohorts, but we did not include this aspect in the evaluation of limitations
We considered five additional limitation criteria, which are relevant for the evaluation of reported prodromal marker associations; (6) diagnosis of idiopathic PD by nonspecialists in movement disorders, only probable PD diagnosis or uncertainties regarding the parkinsonian disease status in ‘‘healthy’’ individuals at baseline; (7) limitations in prodromal marker assessments; (8) reduced generalizability of findings; (9) limitations of statistical analyses, e.g., no appropriate accounting for confounders in the design or analysis; and (10) absent or limited data on the temporal sequence, e.g., duration of marker presence at baseline, or latency period between exposure measurement and onset of PD

Summary

Introduction

While numerous longitudinal cohort studies support the concept of prodromal PD and prodromal markers (e.g., Abbott et al, 2001; Postuma et al, 2015; Schrag et al, 2015), the comparability of study results is hampered by methodological differences (Lerche et al, 2015), such as design, type of assessments and analytical methods. Limitations of individual studies might affect comparability and interpretation of findings. Limitations in these prodromal marker studies have not yet been systematically reviewed. We performed a systematic review of published longitudinal studies investigating prodromal markers in PD to examine the methodological quality of these studies and to identify key areas that could be improved in future research

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Results

Conclusion