Importance: Alpha-synuclein (a-syn) is the main component of Lewy bodies, the pathological hallmarks of Parkinson’s Disease (PD). Oligomeric species of a-syn are thought to arise early in the prodromal phase of PD, exerting toxic effects and propagating aggregated a-syn pathology. The possibility of using saliva - an easily accessible biofluid - to detect seeding-competent a-syn oligomers would represent an important advancement to facilitate the early diagnosis and to monitor progression of PD. Objective: To determine whether saliva can be used for the detection of seeding competent a-syn oligomers with Real-Time Quaking Induced Conversion (RT-QuIC). Design: We performed a prospective diagnostic study with the saliva of de novo diagnosed PD patients and age and sex-matched healthy subjects (HS), enrolled between November 2017 and November 2019. RT-QuIC measurements were performed between October 2018 and December 2019. Setting: The patients were enrolled in one neurological Institution. Follow-up was performed at 4-month intervals for a period of 3 years after performing RT-QuIC. Participants: Forty-one Parkinson’s disease (PD) patients were enrolled in consecutive series of 6 patients each. Diagnosis of PD was performed by clinical evaluation following the Queen Square Brain Bank criteria and confirmed by three different independent movement disorder experts. DAT-Scan was performed when the clinical diagnosis of PD was uncertain. Exclusion criteria included a confirmed diagnosis of neurological disorders different from PD, diabetes mellitus, systemic autoimmune and inflammatory diseases, neoplasms, salivary gland and oral cavity pathologies. Twenty-six control subjects without neurological symptoms were also included in the study. Main outcomes and measures: Salivary a-syn seeding activity was assessed by RT-QuIC. Results: A total of 60 salivary samples from de novo PD and healthy subjects (HS) were analysed. Salivary RT-QuIC demonstrated a good diagnostic accuracy: sensitivity 83.78% (95% CI: 68.86-92.35); specificity 82.61% (95% CI: 62.86-93.02), with a Likelihood Ratio of 4.818. Hierarchical clustering and linear regression showed a statistically significant correlation between increased disease severity (evaluated with motor and non-motor scores) and a greater response in salivary RT-QuIC assay. Conclusions and Relevance: We have shown the possibility to use saliva and RT-QuIC to detect the presence of a-syn seeding competent species to discriminate between PD patients and HS. Further investigations in larger cohorts are needed to confirm the application of salivary RT-QuIC for PD diagnosis and for the assessment of disease severity and progression.

Salivary α-Synuclein RT-QuIC Correlates with Disease Severity in de novo Parkinson's Disease

Vivacqua, Giorgio
Conceptualization
;
2022-01-01

Abstract

Importance: Alpha-synuclein (a-syn) is the main component of Lewy bodies, the pathological hallmarks of Parkinson’s Disease (PD). Oligomeric species of a-syn are thought to arise early in the prodromal phase of PD, exerting toxic effects and propagating aggregated a-syn pathology. The possibility of using saliva - an easily accessible biofluid - to detect seeding-competent a-syn oligomers would represent an important advancement to facilitate the early diagnosis and to monitor progression of PD. Objective: To determine whether saliva can be used for the detection of seeding competent a-syn oligomers with Real-Time Quaking Induced Conversion (RT-QuIC). Design: We performed a prospective diagnostic study with the saliva of de novo diagnosed PD patients and age and sex-matched healthy subjects (HS), enrolled between November 2017 and November 2019. RT-QuIC measurements were performed between October 2018 and December 2019. Setting: The patients were enrolled in one neurological Institution. Follow-up was performed at 4-month intervals for a period of 3 years after performing RT-QuIC. Participants: Forty-one Parkinson’s disease (PD) patients were enrolled in consecutive series of 6 patients each. Diagnosis of PD was performed by clinical evaluation following the Queen Square Brain Bank criteria and confirmed by three different independent movement disorder experts. DAT-Scan was performed when the clinical diagnosis of PD was uncertain. Exclusion criteria included a confirmed diagnosis of neurological disorders different from PD, diabetes mellitus, systemic autoimmune and inflammatory diseases, neoplasms, salivary gland and oral cavity pathologies. Twenty-six control subjects without neurological symptoms were also included in the study. Main outcomes and measures: Salivary a-syn seeding activity was assessed by RT-QuIC. Results: A total of 60 salivary samples from de novo PD and healthy subjects (HS) were analysed. Salivary RT-QuIC demonstrated a good diagnostic accuracy: sensitivity 83.78% (95% CI: 68.86-92.35); specificity 82.61% (95% CI: 62.86-93.02), with a Likelihood Ratio of 4.818. Hierarchical clustering and linear regression showed a statistically significant correlation between increased disease severity (evaluated with motor and non-motor scores) and a greater response in salivary RT-QuIC assay. Conclusions and Relevance: We have shown the possibility to use saliva and RT-QuIC to detect the presence of a-syn seeding competent species to discriminate between PD patients and HS. Further investigations in larger cohorts are needed to confirm the application of salivary RT-QuIC for PD diagnosis and for the assessment of disease severity and progression.
Biomarkers; RT-QuIC; Saliva; alpha-synuclein
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12610/70343
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