SynNeurGe: A proposal for the biological classification of Parkinson’s disease and related Lewy body disorders

  Tweet

Currently, the diagnosis of Parkinson’s disease remains a clinical one based on both inclusion and exclusion criteria. However, it is well known that the underlying degenerative process exists in both the central and peripheral nervous systems for years before patients present with the classical clinical features. Given the ability to define the presence of the characteristic pathogenic features of Alzheimer’s disease (AD) at the earliest stages using assays for beta-amyloid and tau, the development of a biological definition of AD has generated substantial advances in the understanding of the disease and driven the development of novel disease modifying therapy trials that are beginning to bear fruit. In recent years, fluid, tissue, and imaging biomarkers for Parkinson’s disease, most notably the development of seeding amplification assays (SAAs) for pathologic α-synuclein, have placed us in a position that we can now consider a similar biological classification of PD in order to spearhead a new phase of research endeavor. Indeed, these techniques are now sufficiently advanced to allow objective identification of genetic risk, pathological processes, and neurodegeneration, even before overt clinical symptoms have appeared.   

Importantly, Parkinson’s disease is acknowledged as an extremely heterogeneous disorder (1), even with respect to the underlying pathological changes and the involvement of α-synuclein. Rather than simplifying and homogenizing Parkinson’s disease as a pure synuclein-related disorder (indeed, the exact role of α-synuclein in the pathogenesis of PD remains uncertain) any new biological approach to the “disease” (perhaps better considered “diseases”) needs to address and incorporate this heterogeneity; a biological classification is therefore more appropriate than attempting to establish a single biological definition. Characterizing symptomatic patients as well as asymptomatic individuals based on certain biological profiles will have major impact in advancing a broad range of research studies (e.g. epidemiology, neuroimaging, biomarker discovery, clinical trials, etc.) that are currently hampered by limitations of pure clinical classifications, and even studies classifying patients on the basis of single biological criterion (e.g. a pathogenic genetic variant or single neuroimaging feature).

We have entitled this classification scheme “SynNeurGe,” pronounced “synergy,” to highlight the important interactions and relationships between the three central components. Importantly, acknowledging the biological heterogeneity of PD, we incorporate a S-negative category for selected genetic forms of PD that may not demonstrate pathological α-synuclein in the brain using current immunohistochemistry (IHC) techniques. Well-defined clinical (C) criteria “possibly-” or “probably-related” to Parkinson’s disease are then applied to any individuals designated as S+, N+, or G+. 

In our report we have outlined a number of limitations and ethical issues that need to be addressed through further research. For example, many asymptomatic individuals fulfilling criteria for selected biological designations may never develop symptoms of a Lewy body disease and large longitudinal studies will be required to determine the factors that predispose some to develop overt progressive neurodegeneration and others to be protected from this course. We emphasize that the current availability of CSF SAA, skin IHC studies, and DAT scans accentuates the need to proactively develop the biological criteria for research purposes now rather than generating a belated reactive response to the widespread free market application of these tests. 

We believe that this is an initial important step in classifying and characterizing patients at the earliest pathological states, even before the term “disease” could be applied, in order to advance broadly based research efforts on many fronts. The eventual goal of these efforts is the successful development of precision medicine-based effective disease modifying therapies that our patients sorely need.

References

1. Outerio TF, Alcalay RN, Antonini A, et al. Defining the riddle in order to solve It: There is more than one "Parkinson's disease". Mov Disord 2023; 38: 1127-1142.     

2.  Höglinger GU, Adler CH, Berg D, Klein C, Outeiro TF, Poewe W, Postuma R, Stoessl AJ, Lang AE. SynNeurGe: research criteria for a biological classification of Parkinson’s disease. Lancet Neurology 2024; 23:  

Tweet