Neuropathological progression of clinical Parkinson disease subtypes

Many attempts have been made to identify clinical subtypes of Parkinson disease (PD), but little progress has been made in determining whether they are simply a reflection of the clinical heterogeneity of PD or whether they represent different diseases hiding under one rubric. In a recent News & Views article (Clinical Parkinson disease subtyping does not predict pathology. Nat. Rev. Neurol. 15, 189–190 (2019))¹, Alberto Espay and Connie Marras discussed our recent clinicopathological study showing that PD subtyping at diagnosis can provide useful information on subsequent disease progression and survival². They stated correctly that the severity of Lewy and Alzheimer disease (AD) pathologies did not differ between the clinical subtypes but, importantly, they failed to mention that these pathological changes were reached over a considerably shorter disease duration in the diffuse malignant subgroup than in the other subtypes. This was one of the key findings of our study.

All patients with PD, despite differences in the disease course in the early and middle stages, eventually enter an accelerated terminal phase of illness, often associated with falls and cognitive impairment^3,4. By the time of death, most patients with PD have reached an equivalent terminal neuropathological stage but, analogous to clinical progression, the rate of neuropathological deterioration differs among different subgroups, and it was this finding that allowed us to conclude that different neuropathologies were important determinants of clinical PD subtypes². Despite different rates of clinical and neuropathological progression, we could not establish pathological features that would allow a neuropathologist ‘blinded’ to the clinical details to accurately categorize the clinical subtype.

Neuropathological studies have inherent limitations given the inability to serially examine brain tissue over time to evaluate the dynamic neurodegenerative processes, which prevents analysis of differences in pathological severity and distribution among subtypes at earlier stages of the disease. We agree that other important factors such as regional cell loss independent of Lewy and AD neuropathologies must be involved, and we have previously demonstrated that the age of the patient is an important determinant of prognosis and also of clinical subtype definition^2,3.

There is a reply to this letter by Espay, A. J. & Marras, C. Nat. Rev. Neurol. https://doi.org/10.1038/s41582-019-0198-9 (2019).