Staging system predicts early-stage Parkinson’s time to progression
The NSD-ISS system classifies the disease in six stages
A framework called the neuronal alpha-synuclein disease integrated staging system (NSD-ISS) to stage patients in the early stretch of Parkinson’s disease, or who have yet to manifest symptoms, can help predict how quickly they may progress to clinically meaningful milestones.
In a study led by Tanya Simuni, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, and funded by The Michael J. Fox Foundation for Parkinson’s Research (MJFF), researchers identified where patients are in their disease by looking at clinical and biological markers like alpha-synuclein, a protein that forms the toxic clumps called Lewy bodies that are thought to be at the root of Parkinson’s.
“Currently, the field has been using clinically defined diagnostic criteria of Parkinson’s disease or dementia with Lewy bodies and there are no established frameworks of biological and clinical subtyping,” Simuni said in a university news story.
For Simuni, who also directs the Parkinson’s Disease and Movement Disorders Center at Northwestern University, the study “provides the anchors … the framework to validate what we’ve demonstrated to build on longitudinal data and to apply the same framework to the preclinical stages of the disease.”
The study, “Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts,” was published in npj Parkinson’s Disease as a collaborative effort from researchers in industry and academia.
“This was a concerted effort of academicians, people in industry because they need this framework to develop therapeutics in early stages of the disease, regulators, preclinical scientists, advocacy organizations and, very importantly, people with lived experiences,” Simuni said. “This is truly a multi-stakeholder effort.”
Setting stages for Parkinson’s disease
In early Parkinson’s, toxic clumps of misfolded alpha-synuclein accumulate in the brain, causing the death of dopamine-producing nerve cells. Dopamine is involved in motor control and the brain chemical ‘s absence can lead to motor symptoms. Toxic alpha-synuclein clumps can begin to accumulate years before motor symptoms appear, however.
Detecting alpha-synuclein hasn’t been possible in living patients. But last year, the MJFF validated the alpha-synuclein seed amplification assay (aSyn-SAA), a test that can measure the protein in cerebrospinal fluid, the liquid which flows around the brain and spinal cord.
In light of this progress, researchers began to advocate for a more objective approach to define Parkinson’s and its stages by using biological indicators, such as alpha-synuclein and dopamine loss, offering a more precise approach to diagnosis and treatment.
The NSD-ISS system classifies Parkinson’s disease in six stages (0-6). In stages 0-1, most patients show aggregated alpha-synuclein via the aSyn-SAA test and dopaminergic neuron issues using an imaging test called DaTScan. As the disease worsens, motor and nonmotor symptoms emerge, leading to severe impairments and the loss of independence by stage 6.
Here, researchers used data from three different studies: the Parkinson’s Progression Markers Initiative (PPMI), PASADENA (NCT03100149), and SPARK (NCT03318523). Patients with Parkinson’s, those with prodromal, that is, early-stage disease, or healthy people were staged based on biological, clinical, and functional biomarkers, or anchors.
“We first reviewed the landscape of what clinical measures are available in the field that have been applied in [a] majority of the recently completed or conducted studies, and programmatically put together data-informed anchors and then applied those anchors,” Simuni said.
Of 1,741 people, more than half (59%) tested positive for alpha-synuclein toxic clumps. Most patients with sporadic Parkinson’s (93%) were classified as having neuronal alpha-synuclein disease, with 25% in stage 2B, 63% in stage 3, and 9% in stage 4.
The progression rates were faster at higher stages. Patients took 8.3 years, 5.9 years, and 2.4 years to reach clinically meaningful milestones in stages 2B, 3, and 4, respectively. The findings show how the NSD-ISS identifies where patients are in the disease process and predicts how quickly they may progress.
The time to progression can give key insights for treatment planning. Stage 4 patients, for example, are likely to require faster intervention since they progress rapidly, with a median time of 2.4 years to clinically meaningful milestones. The variability in progression times supports the need for personalized care.
Further research is needed to confirm the accuracy of the NSD-ISS and to validate it a useful tool for understanding Parkinson’s biology and its functional impacts, said the researchers, who noted the data “provide an opportunity to build on the current NSD-ISS framework to further inform therapeutic development.”
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