title: Prodromal Markers in Parkinson's Disease: Limitations in Longitudinal Studies and Lessons Learned.
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.
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Heinzel
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roeben
authors.affiliation: School of Social and Community Medicine, University of Bristol Bristol, UK.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lerche
authors.affiliation: Norwegian Centre for Movement Disorders and Department of Neurology, Stavanger University Hospital Stavanger, Norway.
authors.forename: Guido
authors.initials: G
authors.lastname: Alves
authors.affiliation: Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, Department of Medicine, University of Salerno Salerno, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
authors.affiliation: Department of Neurology, University of Homburg Homburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Behnke
authors.affiliation: Department of Neurology and Neuroscience Campus Amsterdam, VU University Medical Centre Amsterdam, Netherlands.
authors.forename: Henk W
authors.initials: HW
authors.lastname: Berendse
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Department of Neurology Nijmegen, Netherlands.
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.affiliation: Institute of Neuroscience, Newcastle University Newcastle Upon Tyne, UK.
authors.forename: David
authors.initials: D
authors.lastname: Burn
authors.affiliation: Department of Neurology, Philipps-University Marburg Marburg, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Dodel
authors.affiliation: Institute of Neurological Sciences, Queen Elizabeth University Hospital Glasgow, UK.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Grosset
authors.affiliation: Oxford Parkinson's Disease Centre and Nuffield Department of Clinical Neurosciences, University of Oxford Oxford, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Hu
authors.affiliation: Institute of Neurogenetics, University of Lübeck Lübeck, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Kasten
authors.affiliation: Clinical and Experimental Neuroscience, Luxembourg Center for Systems Biomedicine Belva, Luxembourg.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, Department of Medicine, University of Salerno Salerno, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Moccia
authors.affiliation: Paracelsus-Elena-KlinikKassel, Germany; Department of Neuropathology, University Medical CenterGöttingen, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.affiliation: Department of Neurology, Philipps-University Marburg Marburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Oertel
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Suenkel
authors.affiliation: Department of Neurology, University of Rostock Rostock, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Walter
authors.affiliation: Department of Medical Epidemiology and Biostatistics and Department of Clinical Neuroscience, Karolinska Institutet Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Wirdefeldt
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Liepelt-Scarfone
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Center for Neurodegenerative Diseases, University of TübingenTübingen, Germany; Department of Neurology, Christian-Albrechts-UniversityKiel, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
keywords: Parkinson’s disease; case-control; clinical; cohort; longitudinal; marker; prodromal; prospective