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.

Keywords: Parkinson’s disease; case-control; clinical; cohort; longitudinal; marker; prodromal; prospective.

Figure 1

Graphical illustration of the prodromal phase with early neurodegenerative changes occurring years or even decades before the clinical diagnosis of Parkinson’s disease (PD) can be made. Risk markers may increase the PD risk without directly being associated with neurodegenerative changes. Only slight loss of neurons due to the normal aging process can be detected in this phase. Prodromal markers represent indicators of the early neurodegenerative process in which neuronal loss is accelerated. This phase may ultimately lead to PD. Risk markers increase the likelihood that an individual may enter the prodromal phase and may finally develop motor PD. Prodromal markers may indicate the ongoing neurodegenerative process and may help to identify those individuals who will likely develop PD in the future.

Figure 2

Frequency of limitations in prodromal PD studies.

Figure 3

Frequencies (in %) of studies with a limitation in the 10 predefined limitation categories. Frequencies are shown for studies with, in total, 1 limitation, 2 limitations and studies with 3 or more limitations.