αSyn SAA as a promising tool for improving early diagnosis and classifying subtypes of PD

08 Jun 2023

A cross-sectional analysis of the Parkinson’s Progression Markers Initiative (PPMI) study revealed that performing α-synuclein (αSyn) seed amplification assay (SAA) on cerebrospinal fluid (CSF) can accurately distinguish patients with Parkinson’s disease (PD) from their healthy counterparts during the early stages of degeneration.1 These findings suggested a crucial and promising role of αSyn SAA in future therapeutic development and identifying PD patients who are at risk of disease condition.1

PD is considered one of the leading causes of neurological disability, affecting 6 million patients globally.2 The diagnostic accuracy for the disease remains suboptimal, with early symptoms of PD being misclassified, leading to a misdiagnosis rate of 7%-35%.2 As such, a novel and accurate diagnostic test is much needed for identifying PD. Among the potential candidates, αSyn SSA is constantly being highlighted since the accumulation of αSyn aggregates in the substantia nigra and other areas of the brain is the pathological hallmark of the disease.3 Small-scale studies have established αSyn SAA’s capability in screening participants with PD and individuals from the at-risk groups.4,5

The PPMI study was a large-scale, international observational study that aimed to define the clinical and biological markers for the determination of heterogeneity and progression in PD.1 The study recruited patients from outpatient neurology practice at academic centers in the United States (US), Canada, Israel and several European countries.1 Participants in this study were included in one of the five PPMI cohorts (n=1,123), i.e., participants with PD, healthy controls, participants with parkinsonism but with scans without evidence of dopamine deficiency (SWEDD), participants who were prodromal (including those with RBD or hyposmia), and non-manifesting carriers of genetic variants associated with PD.1 All were recruited between July 7, 2010 and July 4, 2019.1 Sensitivity and specificity of αSyn SSA were calculated.1

Results revealed that αSyn SAA possessed an overall sensitivity of 87.7% (95% CI: 84.9-90.5) in the detection of all PD.1 The specificity for healthy controls was 96.3% (95% CI: 93.4%-99.2%).1 Among the genetic PD subgroups, patients with glucocerebrosidase (GBA)- associated PD have shown the highest proportion of positive αSyn SAA results (95.9%; 95% CI: 90.4-100.0), followed by sporadic PD (93.3%; 95% CI: 90.8-95.8).1 For sporadic PD with typical olfactory deficit, the sensitivity was found to be 98.6% (95% CI: 96.4%-99.4%).1 The sensitivities were lower for the subgroups with leucine-rich repeat kinase 2 (LRRK2)-associated PD and those with sporadic PD without olfactory deficit, representing 67.5% (95% CI: 59.2%-75.8%) and 78.3% (95% CI: 69.8%-86.7%), respectively.1 Hyposmia remained the most prevalent clinical feature associated with positive αSyn SAA results, possessing a sensitivity of 97.2% (95% CI: 95.5-98.8) among participants with both PD and hyposmia.1

In summary, the large-scale study has demonstrated high sensitivity and specificity of αSyn SAA in classifying people with PD, providing invaluable information prior to diagnosis.1 These findings suggested a promising role of αSyn SAA in identifying the at-risk groups and subgroups of people with Parkinson’s disease and fostering future therapeutic development.1

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