Parkinson’s disease (PD) research is shifting from clinical definitions to a biologically based classification system, driven by novel biomarkers and a deeper understanding of the disease's complex pathology, particularly in the prodromal (pre-symptomatic) phase. This shift is crucial for developing disease modifying therapies (DMTs) and improving disease modelling.
The need for a biological classification of PD
Historically, PD and related Lewy body disorders have been defined primarily by clinical features, leading to challenges such as slow diagnosis, heterogeneity, and lack of objectivity. This reliance on clinical symptoms often means that DMT trials are conducted when significant neurodegeneration has already occurred, hindering efforts to develop effective treatments.
Proposed biological classification systems for PD
Two prominent biology-based criteria for PD have recently been proposed:
- SynNeurGe framework: This system uses a three-component biological system linked to a clinical component to classify PD and related Lewy body disorders. The components are:
- S (Synucleinopathy status): Indicates the presence or absence of pathological α-synuclein using methods like Seed Amplification Assays (SAA) and skin biopsies.
- N (Neurodegeneration status): Provides evidence of underlying neurodegeneration through neuroimaging procedures such as DAT imaging, metabolic FDG-PET, and cardiac MIBG SPECT.
- G (Genetic status): Documents the presence or absence of pathogenic gene variants using methods like genetic testing.
- C (Clinical status): Defined by either a single high-specificity clinical feature or multiple lower-specificity clinical features, determining if they are attributable to the underlying biological process of PD.
- Neuronal α-Synuclein Disease (NSD) concept, including the Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS): This concept defines neuronal α-synuclein disease as the presence of pathological α-synuclein and stage-dependent evidence of dopaminergic neuronal dysfunction. It uses S and D as primary biological anchors, with genetic status (G) playing a supporting role, and functional impairment defining later stages.
Similarities and differences between SynNeurGe and NSD-ISS
Both systems aim to improve early diagnosis and facilitate the development of DMTs. However, they differ in terminology, aims, methodology, and the scope of PD they encompass. SynNeurGe is broader and more flexible, while NSD-ISS is more restricted and focused on early sporadic PD.
Continued development of biological classifications of PD
Both frameworks are expected to evolve over time, incorporating advancements in biomarkers, non-invasive testing, new biological anchors, and more longitudinal data. Understanding the prodromal features, the progression of pathology, and the intersectionality of different biological factors will be crucial for refining these classifications.
Use of biological classifications in research
Both SynNeurGe and NSD-ISS can be used to produce more homogeneous clinical trial populations by removing individuals who are unlikely to have early-stage PD. This can improve the power of clinical trials and accelerate the development of DMTs. The choice of classification will depend on the specific research question being addressed.
Ethical implications of biological classification for PD
The transition to biological diagnosis, especially in asymptomatic individuals, raises ethical concerns such as limited understanding of natural history, lack of approved DMTs, diagnostic inaccuracy, commercialization, and technological demands. Addressing these concerns requires careful consideration and the involvement of key stakeholders.
Impact of biological classifications on preclinical research
The shift towards a biological classification of PD will drive a deeper understanding of the different types of disease processes underlying the disease. This will allow for the development of more accurate animal models and the identification of new therapeutic targets. Understanding the initial cell loss and the specific biological processes affected at different stages of the disease will be crucial for developing effective DMTs.
Impact on developing symptomatic therapies
While animal models have been successful in developing symptomatic therapies for motor symptoms, the development of therapies for non-motor symptoms may require a greater incorporation of the emerging biology of the disease. The heterogeneity of non-motor symptoms and the limited understanding of their underlying pathology present challenges that need to be addressed.
