Inter-relationship of the age of onset to the concept of brain-first versus body-first Parkinson's disease

The subtyping of Parkinson's Disease (PD) into brain-first and body-first PD has a powerful neuropathological, neuroimaging and clinical basis, supported by most relevant subsequent studies that have examined its validity. Here, we put forward the idea that the previous classification into early and late onset PD may be related to this categorization. The mean age of motor onset in brain-first PD may be up to 10 years earlier than body-first PD. Early onset PD has features related to brain-first PD, including relative clinical and nigrostriatal neurodegeneration asymmetry and a relatively restricted motor phenotype. In fact, PD as described by James Parkinson, could represent both early onset and brain-first PD, accounting for the famous phrase "senses and intellect uninjured". We suggest here that, at the population level, age of onset could be used as a proxy for brain-first vs body-first PD, notwithstanding the lack of a direct one-to-one correlation and of a clear dichotomy in early vs. late onset PD, which rather represents a continuum. This would enable large scale population studies into the underlying genetic and epidemiological basis of these presumed separate nosological entities. Along these lines, there are some indications of a divergent exposure and genetic basis in early vs. delayed onset PD, and body-first vs. body-first PD respectively. Thus, studies of the etiopathological basis of PD could examine data sets with clinical data limited to age of onset, keeping in mind that within the overall concept of sporadic PD there may be two qualitatively different disease processes.