Do Parkinson's Disease clinical subtypes really exist?

Introduction. Parkinson's Disease (PD) is a highly heterogeneous entity in terms of clinical manifestations, progression, and treatment response. This variability has given rise to the hypothesis that different clinical subtypes of the disease exist. State of the art. To date, several clinical subtypes have been described, mostly based on different clinical features, and sometimes with the support of biomarkers, either fluid, neuroimaging, or neurophysiological. The most homogeneous subtypes detected are a 'benign subtype', characterised by younger age at onset, mild non-motor symptoms, and a slower rate of disease progression, and a 'malignant subtype', which features an older age at onset, a higher burden of non-motor symptoms, and faster disease progression. Clinical implications. Despite extensive research, none of the subtypes identified so far seem to be biologically supported, so clinical subtyping does not elucidate PD aetiology and does not allow for the prediction of prognosis or treatment response. This study was aimed to review the literature on this topic and to examine the studies on PD subtyping. We also reviewed the proposed biomarkers for a biological classification of PD, and outlined the role of genetics and pathology within this context. Future directions. In light of the recent proposal of a biological classification of PD, which might overcome the limits of the clinical diagnosis, PD subtyping should hopefully shepherd researchers towards a biological approach, also aided by recent advances in the field of biomarkers.