In Parkinson disease (PD), pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop and enable clinical diagnosis. In this prodromal phase, risk and prodromal markers can be used to identify individuals who are likely to develop PD, as in the recently updated International Parkinson and Movement Disorders Society research criteria for prodromal PD. However, increasing evidence suggests that clinical and prodromal PD are heterogeneous, and can be classified into subtypes with different clinical manifestations, pathomechanisms and patterns of spatial and temporal progression in the CNS and PNS. Genetic, pathological and imaging markers, as well as motor and non-motor symptoms, might define prodromal subtypes of PD. Moreover, concomitant pathology or other factors, including amyloid-β and tau pathology, age and environmental factors, can cause variability in prodromal PD. Patients with REM sleep behaviour disorder (RBD) exhibit distinct patterns of α-synuclein pathology propagation and might indicate a body-first subtype rather than a brain-first subtype. Identification of prodromal PD subtypes and a full understanding of variability at this stage of the disease is crucial for early and accurate diagnosis and for targeting of neuroprotective interventions to ensure efficacy.
Key points
• Heterogeneity of Parkinson disease (PD) starts in the prodromal phase.
• Pathological spread, imaging markers and the onset and progression of motor and
non-motor symptoms are variable in prodromal PD.
• The variability in clinical phenotype suggests that subtypes of prodromal PD can be defined.
• Possible subtypes of prodromal PD are REM sleep behaviour disorder subtypes, brain-first and body-first subtypes, genetic subtypes and biological subtypes.
• Variability in prodromal PD must result from different pathophysiological mechanisms; defining prodromal subtypes is the first step to identifying the biological difference.
Berg, D., Borghammer, P., Fereshtehnejad, SM. et al. Prodromal Parkinson disease subtypes — key to understanding heterogeneity. Nat Rev Neurol (2021). https://doi.org/10.1038/s41582-021-00486-9
https://www.nature.com/articles/s41582-021-00486-9
