According to a new study in NPJ Parkinson’s disease, investigators led by Arthur C. Nielsen, Junior research professor of Parkinson’s disease and movement disorders, Tanya Simuni, MD, defined new biological and clinical biomarkers to better define patients with different stages of Parkinson’s disease and related dementia-Lewy body dementia.
“There are no established frameworks of biological or clinical subtyping: Currently, these have been defined clinically, based on the diagnosis of Parkinson’s disease or dementia with Lewy bodies,” Simuni, who also directs the Parkinson’s disease and movement disorders center and is chief of movement disorders in the Ken and Ruth Davee Department of Neurology, said.
“The anchors and framework provided here, allow us to look at building on the longitudinal data and applying the same framework to the preclinical stage of the disease this paper provides the significance of it,” Simuni said. Neuronal alpha-synuclein disease (NSD) is a neurodegenerative disorder characterized by the accumulation of extranuclear alpha-synuclein protein in brain neurons (Lewy bodies) and elsewhere in the brain, such as in glial cells where it causes neurodegeneration, and that can occur as Parkinson’s disease or Lewy body dementia.
Until recently, there has been no framework to define either disease before symptom onset. Earlier work led by Simuni, which was published in The Lancet Neurology, had most recently developed the neuronal alpha-synuclein disease integrated staging system (NSD-ISS) to identify patients with Lewy body pathology. Simuni and her team in the current study sought to field and use disease-stage-specific, biological, and data-informed definitions of the NSD-ISS.
Participant data from three independent studies were evaluated: garnered insights from the Parkinson’s progression markers initiative (PPMI), the phase 2 trial of anti α-Synuclein antibody in early Parkinson’s disease (PASADENA) study, and the study of Parkinson’s disease of antibody to alpha-synuclein by Rinat research (SPARK)study. Patients were defined and staged in the cohorts having Parkinson’s disease, prodromal (early stage) disease, or healthy controls based on biological, clinical, and functional biomarkers (“anchors”) at baseline. “So first we took the landscape in the field of what clinical measures are out there, that have been applied across the majority of the recently completed or ongoing studies and programmatically put together data-informed anchors and then applied those anchors to the PPMI, PASADENA, and SPARK cohorts,” Simuni said.
Data from 1,741 participants in alpha-synuclein seed amplification assays (a detection of abnormal protein levels) was collected across the three studies. Approximately 60% of these participants were alpha-synuclein positive and consistent with NSD. In sporadic Parkinson’s disease patients, 93%had NSD, and the distribution for stages 2B, 3, and 4 disease was 25%, 63%, and 9%, respectively.
The baseline stages 2B, 3, and 4 took an average of 8.3, 5.9, and 2.4 years respectively to reach a clinically meaningful outcome. Simuni says, the results more accurately describe the baseline heterogeneity of individuals currently classified as early Parkinson’s disease, and future research is needed to validate these findings in longitudinal studies.
They provided strong support for the concept of the biological definition and staging framework both to screen the potential study participants before the symptoms and to screen participants with more homogenous functional impairment and disease progression at the time of symptom onset. The authors can take advantage of the opportunity to build on the current NSD-ISS framework to further inform therapeutic development, they add.
“It was a concerted effort of academicians, people in the industry because they needed the framework to develop therapeutics early in the disease process, regulators, preclinical scientists, advocacy organizations, and most importantly people with lived experiences,” Simuni said.
Reference: Dam T, Pagano G, Brumm MC, et al. Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts. NPJ Parkinsons Dis. 2024;10(1):178. doi:10.1038/s41531-024-00789-w
