AlphaSyn-SAA test accurately detects Parkinson’s, study finds
Discovery lauded as 'revolutionizing every aspect of research and care'
A test called the alpha-synuclein seed amplification assay, or alphaSyn-SAA, can detect Parkinson’s disease with high accuracy, a new study reveals.
The research was conducted as part of the Parkinson’s Progression Markers Initiative (PPMI), an international study led by the The Michael J. Fox Foundation for Parkinson’s Research (MJFF).
“It would be difficult to overstate the implications of this discovery,” Deborah Brooks, CEO of the MJFF, said in a press release. “With development and scaling, [alpha]Syn-SAA can usher in the era of objectively and biologically defining Parkinson’s disease — revolutionizing every aspect of research and care.”
“There are many ways I am involved with the work of the Foundation, but I come to this result first and foremost as a Parkinson’s patient,” said Michael J. Fox. “I am deeply moved by this breakthrough and endlessly grateful to the researchers, study participants and funders who have endeavored to bring us this far,” he said.
“When we started PPMI, we weren’t casting about for fish — we were going after a whale,” Fox added. “Now, here we are. Together we are making a cure for Parkinson’s inevitable.”
The study, “Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using [alpha]-synuclein seed amplification: a cross-sectional study,” was published in The Lancet Neurology.
A molecular hallmark of Parkinson’s disease is the formation of toxic clumps of the protein alpha-synuclein inside the nervous system, which are thought to play a central role in driving disease progression. Toxic alpha-synuclein spreads in a prion-like fashion, meaning that clumps in one part of the brain can trigger more clumps to form in neighboring areas.
The alphaSyn-SAA assay is done on a sample of a patient’s cerebrospinal fluid (CSF) — the fluid around the brain and spinal cord — collected through the spine via a procedure called a lumbar puncture, or spinal tap. The assay involves adding a seed of clumped alpha-synuclein to a sample of CSF, then seeing whether the clumping spreads in the prion-like manner characteristic of Parkinson’s.
The technology originally was developed via a collaboration between the MJFF and a team of scientists at the University of Texas. The Texas team has since launched the company Amprion, which is marketing a version of the alphaSyn-SAA test under the brand name SYNTap.
A notable limitation of the technology is that the test alone can’t distinguish between Parkinson’s and other disorders characterized by alpha-synuclein clumps, such as dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). But the test may aid clinicians in making a diagnosis.
“The Michael J. Fox Foundation has always recognized the indisputable need for biomarkers of Parkinson’s disease, and has relentlessly pursued them as a mission-critical goal,” Brooks said.
In this study, alphaSyn-SAA results were compared for 1,123 people enrolled in the PPMI study. About half of these participants had diagnosed Parkinson’s disease, including 373 patients with sporadic disease, 123 with mutations in the LRRK2 gene, and 49 with mutations in the gene GBA. Mutations in these genes are associated with a higher risk of developing Parkinson’s disease.
The rest of the participants included 163 healthy controls and 310 non-manifesting carriers (people who have a Parkinson’s-associated mutation in LRRK2 or GBA, but did not have any symptoms of Parkinson’s at the time of testing).
There also were 54 participants who had symptoms of Parkinson’s but no signs of disease-typical issues with dopamine activity on brain scans, a condition referred to as SWEDD (scans without evidence of dopamine deficiency).
Another 51 patients had been diagnosed with REM sleep behavior disorder (RBD) or hyposmia (loss of smell). These conditions are considered prodromal for Parkinson’s, meaning they often appear as an early disease manifestation prior to the development of diagnosable symptoms.
“To our knowledge, this is the largest report of comparative data from a cohort of participants with Parkinson’s disease, healthy controls, individuals with clinical syndromes prodromal to Parkinson’s disease (hyposmia and RBD), and non-manifesting carriers,” the researchers wrote.
Results highly sensitive
Results showed that, across all these groups, the alphaSyn-SAA test was generally accurate for detecting Parkinson’s, with a sensitivity of 87.7%. That means nearly nine of 10 people with diagnosed Parkinson’s had a positive test.
Among healthy patients, the positive rate was much lower at just 4%, meaning that 96.3% of healthy patients tested negative. The positive rate was slightly higher among individuals with SWEDD, but still more than 90% had a negative test result. According to researchers, this is “supportive of a model in which a positive [alpha]-synuclein AAA result could precede abnormal DAT imaging,” this way extending the time-frame in which it could be possible to intervene with preventive therapies.
By comparison, the vast majority (86%) of patients with prodromal disease had a positive test result. This suggests the test may be able to help detect the earliest stages of Parkinson’s-related damage, though the researchers cautioned that additional long-term study is needed to test this idea definitively.
While the test was highly sensitive for detecting Parkinson’s overall, results suggested that the accuracy of the test varied based on genetic subtype of Parkinson’s. Specifically, among patients with sporadic Parkinson’s or those with mutations in the GBA gene, more than 90% of patients tested positive on the alphaSyn-SAA test.
However, for patients with LRRK2 mutations, the positive rate was markedly lower: 67.5%. The positive rate was particularly low in female patients (55.2%) with LRRK2 mutations, whereas it was somewhat higher for male patients (78.5%).
The test also appeared more sensitive among patients with smell loss. More than 97% of Parkinson’s patients with hyposmia tested positive on the alphaSyn-SAA, compared to just 63% of patients whose sense of smell was intact.
By combining these findings, the researchers were able to outline the test’s accuracy for specific patient subgroups. For example, the positive rate was 98.6% in patients with sporadic Parkinson’s and hyposmia. For female patients carrying the LRRK2 mutation with intact smelling ability, it was 12.5%.
Among non-manifesting carriers, only 9% of those carrying a mutation in the LRRK2 gene and 7% of those carrying a mutation in the GBA gene were positive for the alphaSyn-SAA test.
These results suggest that symptoms such as olfactory loss appear closer to the onset of motor symptoms, and that the aggregation of alpha-synuclein in the spinal fluid occurs as part of the natural evolution of Parkinson’s, which ultimately results in the appearance of symptoms.
Autopsy data were available for 15 of the Parkinson’s patients who had died since enrolling in the study. All but one of these patients tested positive on alphaSyn-SAA, and had evidence of toxic alpha-synuclein clumps in their brains. The lone exception, who carried the LRRK2 mutation, was negative on the alphaSyn-SAA test and also did not have alpha-synuclein clumps in the brain upon autopsy.
These autopsy findings suggest that the alphaSyn-SAA test is accurately reflecting the disease-related spread of alpha-synuclein protein, as it is designed to do.
The findings “have immediate implications for clinical trial design,” the researchers said, since they imply that for the first time trials will be able to specifically select whether to include patients who do or do not have evidence of alpha-synuclein clumping.
“Validation of this biomarker launches a new, biological era in Parkinson’s research,” said Kenneth Marek, MD, principal investigator for PPMI at the Institute for Neurodegenerative Disorders in Connecticut.
“Using [alpha]Syn-SAA, we are already unlocking new understanding of Parkinson’s, which will transform every aspect of drug development and ultimately clinical care. We will rapidly be in a position to test new therapies in the right populations, target the right therapy to the right patient at the right time, and launch studies of agents with potential to prevent Parkinson’s disease altogether,” Marek said. “This is what PPMI was built to do, and we are especially grateful to the thousands of study participants whose contributions have enabled this watershed moment.”