The proposed NSD-ISS staging system for Parkinson's disease, focusing on neuronal α-synuclein pathology, aims to enhance trial design and drug development.
A published paper from patient, research, and industry leaders proposed a new staging system by which Parkinson disease (PD) is defined, using neuronal α-synuclein (n-αsyn) pathology, considered a hallmark for the disease, instead of clinical symptoms. Otherwise known as the neuronal α-synuclein disease integrated staging system (NSD-ISS), this system is currently intended for research use only, with the goal to enhance trial design and improve drug development.1,2
The NSD-ISS integrates 2 core biomarkers: aggregated αsyn and dopamine dysfunction. The staging system starts with stages 0-1, which occur without symptoms and are defined by the presence of pathogenic variants in the SCNA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). Stages 1 and 2 are based on objective biomarkers, while stages 3-6 require these biomarkers and progressive motor and other nonmotor symptoms.
Lead investigator Tanya Simuni, MD, FAAN, director of the Parkinson’s Disease and Movement Disorders Center at Northwestern University, and colleagues published the new framework in The Lancet Neurology; however, it would not have been possible without previous research published in 2023. Funded by the Michael J. Fox Foundation, the analysis, considered the largest for an α-synuclein seed amplification assay to date, further validated its role in the biochemical diagnosis of PD. In a cohort of more than 1100 participants, the sensitivity of the assay for PD was 87.7% (95% CI, 84.9-90.5), with even increased sensitivity in sporadic PD with typical olfactory deficit (98.6%; 95% CI, 96.4-99.4).
In stages 3-6, the severity of functional impairment defines each progressive stage. “Although this staging system is grounded on the neuronal α-synuclein disease biological framework, establishing the degree of functional impairment using a data-driven approach is necessary for therapeutic development and other applications of the NSD-ISS,” the study authors wrote. In these stages, functional impairment qualitatively is described as slight, mild, moderate, and severe, in ascending order.
In the paper, the authors note that n-αsyn disease is a continuum, and that an individual in a given stage is presumed to have passed through all preceding stages, beginning with stage 1A. Although a transition from stage 1 to stage 2 may not be observed in a patient, depending on the timing of assessment, the NSD-ISS framework will enable studies to investigate the timing for progression from each stage to the next and the key additional biological determinants that might influence the rate of progression.
Although early in its infancy, the group of investigators believe that data derived from several prominent rating scale assessments in prospective cohort studies and clinical trials will be used to define thresholds for stages 3-6, similar to the Huntington’s disease Integrated Staging System. In addition, the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Parts I and II, widely used to measure functional impairment, would be considered a starting point; however, investigators expressed qualms about its limited sensitivity to detect changes in function in early disease stages.
The paper also acknowledged that individuals with n-αsyn might have a range of clinical syndromes, and that in most cases, these syndromes will overlap, and contributions from motor and non-motor features will produce a cumulative effect on functional impairment. Clinical presentations arising from n-αsyn disease include n-αsyn-driven motor parkinsonism and cognitive impairment–currently diagnosed as PD, PD dementia, or dementia with Lewy bodies based on clinical diagnostic criteria. REM-sleep behavior disorder, dysautonomia, and other neuropsychiatric symptoms may also predominate as well.
"Although the NSD-ISS provides a unifying biological definition and staging, recognition of clinical syndromes is important to guide symptomatic management, family support, and education," Simuni et al wrote.2 "Another important implication of the biologically based framework of the NSD-ISS is that a clinical diagnosis of prodromal Parkinson's disease, Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies is neither sufficient nor necessary for a neuronal α-synuclein disease diagnosis."