A new technique that could assist in the early detection of Parkinson’s disease by identifying the accumulation of abnormal protein deposits has been discovered, according to research published in The Lancet Neurology journal.
The technique, called α-synuclein seed amplification assay (αSyn-SAA), could play a significant role in the clinical diagnosis and characterization of the disease.
The study has revealed that αSyn-SAA can accurately detect individuals with Parkinson’s disease and also identify those who are at risk of developing the disease and those who exhibit early, non-motor symptoms before the diagnosis.
Parkinson’s disease is characterized by the presence of misfolded α-synuclein protein aggregates in the brain, which this new technique can detect.
The findings of the study “suggest that the αSyn-SAA technique is highly accurate at detecting the biomarker for Parkinson’s disease regardless of the clinical features, making it possible to accurately diagnose the disease in patients at early stages,” says co-author Luis Concha.
“Moreover,” according to the author, the findings “indicate that misfolded α-synuclein is detectable before dopaminergic damage in the brain is about to be observed by imaging, suggesting ubiquitous spread of these misfolded proteins before substantial neuronal damage has occurred.”
The latest study on Parkinson’s disease is the most extensive evaluation of the diagnostic potential of αSyn-SAA to date. While earlier studies have demonstrated that αSyn-SAA can effectively differentiate between individuals with Parkinson’s disease and those without, no comprehensive studies covering a broad range of carefully chosen participants have been conducted until now. The research team examined the usefulness of αSyn-SAA in identifying the underlying heterogeneity in individuals with Parkinson’s disease and its ability to detect early indications of the condition. They utilized data from the Parkinson’s Progression Markers Initiative (PPMI) cohort, which consisted of 1,123 participants, including individuals diagnosed with Parkinson’s disease and at-risk individuals with gene variants (GBA and LRRK2) associated with the disease.
The study also involved the participation of prodromal individuals who exhibited early, non-motor symptoms like sleep disturbance or loss of smell that could be indicative of Parkinson’s disease. However, they had not yet received a diagnosis and did not show any of the characteristic motor symptoms such as muscle stiffness or tremors that appear later in the disease’s progression. The inclusion of prodromal participants aimed to assess whether the αSyn-SAA technique could predict the onset of Parkinson’s disease as well as aid in the diagnosis of individuals with established symptoms.
The study involved analyzing samples of cerebrospinal fluid from each participant, which surrounds the brain and spinal cord, using the innovative αSyn-SAA technique. This groundbreaking method amplifies minute quantities of misfolded α-synuclein protein aggregates present in samples from individuals with Parkinson’s disease to the point where they can be detected using standard laboratory techniques.
The results of the analyses demonstrate that αSyn-SAA can accurately identify people with Parkinson’s disease, with positive outcomes in 88% of all participants with a diagnosis, which included both sporadic and genetic cases.
Individuals with sporadic cases of Parkinson’s disease, which have no known genetic cause, had positive αSyn-SAA results in 93% of cases. However, there were variations in results for those with genetic forms of the disease. Among individuals with the GBA variant, 96% had a positive αSyn-SAA outcome, while only 68% of those with the LRRK2 variant showed positive results.
The majority of prodromal participants showed positive αSyn-SAA results, indicating the presence of α-synuclein protein aggregates despite not yet having received a Parkinson’s disease diagnosis. Among those recruited based on their loss of smell, 89% (16/18 participants) had positive αSyn-SAA outcomes. Similarly, in individuals with REM sleep behavior disorder, a sleep disorder that is known to be an early indicator of Parkinson’s disease, positive αSyn-SAA results were found in 85% (28/33) of cases. No other clinical features were linked to a positive αSyn-SAA outcome.
Among the participants who were carriers of LRRK2 or GBA variants but had not received a diagnosis of Parkinson’s disease or did not show prodromal symptoms, which are referred to as non-manifesting carriers (NMCs), 9% (14/159) and 7% (11/151), respectively, showed positive results from the αSyn-SAA technique.
It is worth noting that a majority of prodromal participants and non-manifesting carriers who tested positive for αSyn-SAA had brain scans that did not show a decrease in the anticipated number of dopamine-producing nerve cells, which is a biomarker signature present even before a diagnosis of Parkinson’s disease is made. This result suggests that the accumulation of α-synuclein protein aggregates may serve as an early indication of disease onset.
According to the study, the clinical feature that demonstrated the strongest correlation with a positive αSyn-SAA result was the loss of smell, which is one of the most prevalent symptoms among both prodromal individuals and those with a Parkinson’s disease diagnosis. Among all participants with Parkinson’s disease who had experienced a loss of smell, 97% had a positive outcome from the αSyn-SAA technique, as opposed to only 63% of those whose sense of smell had not been affected.
Dr. Tanya Simuni, a study author from Northwestern University (U.S.), emphasizes that while the loss of smell appears to be a robust predictor of Parkinson’s disease, the study identified individuals with positive αSyn-SAA results who had not yet experienced a loss of smell. This suggests that α-synuclein pathology may be present even before the sense of smell is measurably impacted. The study only analyzed patients at a specific point in time, and further research is necessary to understand how patients’ sense of smell may alter over time and how it relates to the accumulation of α-synuclein protein aggregates in the brain.
The study findings also showed that certain discrepancies existed in the αSyn-SAA results based on age and sex, particularly in individuals with an LRRK2 mutation. The outcomes indicated that 79% of male Parkinson’s disease participants with an LRRK2 variant had a positive αSyn-SAA result, compared to 55% of females. Moreover, people with an LRRK2 variant and negative αSyn-SAA results tended to be older (69 years versus 62 years) than those with positive αSyn-SAA results. In contrast, there were no differences in results between males and females with sporadic or GBA-associated Parkinson’s disease.
The study also analyzed autopsy data for 15 participants, all of whom had received a Parkinson’s disease diagnosis during their lifetime. The results revealed that 14 of them exhibited typical pathology and were αSyn-SAA positive. The only αSyn-SAA negative case was an individual who did not experience a loss of smell during their lifetime and also carried the LRRK2 variant.
The authors of the study have acknowledged certain limitations in their research. They have stated that larger sample sizes would enhance the analysis, allowing for the overcoming of issues such as skewed data and insufficient sample numbers for some participant groups. The analyses presented in the study are all cross-sectional, but utilizing the PPMI samples collected over time could enable future studies to assess changes over specific periods. Additionally, longer-term research is necessary to investigate further the variations in αSyn-SAA outcomes between people with diverse genetic forms of Parkinson’s disease.
Professors Daniela Berg and Christine Klein from University Hospital Schleswig-Holstein, Germany, who were not involved in the study, have commented on the significance of the findings.
They highlighted that the study demonstrated how αSyn-SAA could detect the early signs of Parkinson’s disease, even before other clinical or biomarker changes could be detected. They stated that this finding provides the groundwork for “a biological diagnosis of Parkinson’s disease.”
To fully leverage the potential of αSyn-SAA, Berg and Klein suggest that blood tests will need to be developed. They noted that although the “blood-based method” requires further refinement for scalability, the αSyn-SAA technique is “a game-changer in Parkinson’s disease diagnostics”, research, and treatment trials.
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