Novel Test to Enable Early Detection of Parkinson’s Disease

Currently, the diagnosis of PD primarily depends on neurological examinations and patient medical history. Notably, when PD symptoms become clinically evident, irreversible brain damage has usually already occurred. In the absence of specific blood or laboratory tests for diagnosing PD, especially in 90% of patients without a known genetic predisposition, researchers have now developed a breakthrough molecular assay platform. This platform has shown promise in detecting and quantifying single ⍺-synuclein fibrils, which are critical in the pathology of PD and other related neurodegenerative disorders, known collectively as ⍺-synucleinopathies.

PD, along with multiple system atrophy (MSA) and dementia with Lewy bodies, are part of a group of neurological disorders characterized by the pathological aggregation of ⍺-synuclein protein into toxic fibrils. These fibrils disrupt numerous neurological functions and lead to neuronal cell death. Patients with these ⍺-synucleinopathies exhibit overlapping neurological symptoms, complicating the differentiation of these disorders for treatment. Current treatments for these conditions focus on symptom relief rather than addressing the underlying disease mechanisms. A team from Brigham and Women’s Hospital (Boston, MA, USA) and the Wyss Institute (Boston, MA, USA) has engineered what is known as “digital seed amplification assays” (digital SAAs). These assays are capable of detecting single ⍺-synuclein fibrils in brain tissue and fluid samples.

The researchers utilized mini-compartments and immunocapture strategies to develop various diagnostic assays for detecting ⍺-synuclein fibrils in patient samples. In these dSAAs, individual fibrils are isolated within engineered microcompartments. These fibrils then serve as seeds to grow into larger, easily detectable, and countable fluorescent aggregates. Alongside further optimizing these assays for diagnostic applications to differentiate between ⍺-synuclein fibrils in PD, MSA, and dementia with Lewy bodies, the research team is investigating the platform's potential for drug screening. They demonstrated the effectiveness of a small molecule inhibitor of ⍺-synuclein aggregation using the digital SAA, noting the assay's ability to distinguish between different fibril morphologies.

“Our digital SAAs present a critical technological advance with the potential to turn pathological ⍺-synuclein into an early biomarker for this class of neurodegenerative diseases,” said co-first author Tal Gilboa, Ph.D., a postdoctoral research fellow in the Walt lab. “But work remains to be done. Our current strategies worked well on brain tissue samples from PD and MSA patients, but there’s room to improve their sensitivities so that we can meet the criteria for clinical diagnostic testing, and, hopefully, detect ⍺-synuclein fibrils in blood and other biological fluids.”

Related Links:
Brigham and Women’s Hospital
Wyss Institute