Diagnostic Value of Salivary Real‐Time Quaking‐Induced Conversion in Parkinson's Disease and Multiple System Atrophy

Luan, Mingyue; Sun, Yan; Chen, Jing; Jiang, Yanyan; Li, Fan; Wei, Luhua; Sun, Wei; Ma, Jinling; Lu, Song; Liu, Jianghong; Liu, Bing; Pei, Yaohua; Wang, Zhaoxia; Zhu, Li; Deng, Jianwen

doi:10.1002/mds.28976

Cited by 53 publications

(37 citation statements)

References 17 publications

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“…To date, only one study is available, reporting the diagnostic accuracy of α-syn SAAs in saliva samples collected from patients with PD and MSA. 38 In this work, SAAs produced good results in discriminating PD and MSA from controls (PD: sens 76% and spec 94.4%; MSA: sens 61.1% and spec 94.4%).…”

Section: α-Syn Saas In Easily Accessible Biological Matricesmentioning

confidence: 58%

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α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

et al. 2022

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Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiological role in its onset and progression. Although neuropathological changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Since α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in PD patients would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis.Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt Jakob disease. These techniques enable the detection of minimal amounts of prions in cerebrospinal fluid (CSF) and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded α-syn in CSF, olfactory mucosa, submandibular gland biopsies, skin and saliva, of patients with PD and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLB) from control subjects, even in the prodromal stages of the disease. In terms of differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from non-synucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (PD, DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.

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Section: α-Syn Saas In Easily Accessible Biological Matricesmentioning

confidence: 58%

“…A significantly different seeding activity has been observed also in saliva from patients with MSA and PD, able to differentiate the 2 disorders with 61% sensitivity and 94% specificity (Table 3). 38…”

Section: α-Synuclein Saasmentioning

confidence: 99%

α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

et al. 2022

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“…Interestingly in prodromal DLB 5/5 nasal brushing samples seeded positive reactions (Perra et al, 2021 ), which seems more promising than the Stefani et al ( 2021 ) study on iRBD, albeit with more limited numbers and a different prodromal phenotype. Very recently, RT-QuIC on saliva has demonstrated 76% sensitivity in distinguishing clinically diagnosed PD patients (57/75 positive) and 61.1% sensitivity in distinguishing clinically diagnosed MSA patients (11/18 positive) from non-neurodegenerative healthy controls, with 94.4% specificity (34/36 controls testing negative; Luan et al, 2022 ). In all of these studies, relatively low numbers and a lack of neuropathological confirmation of clinical diagnosis are limitations.…”

Section: Role Of Protein Aggregation With Seed Amplification Assays I...mentioning

confidence: 99%

The Future of Seed Amplification Assays and Clinical Trials

Coysh

Mead

2022

Front. Aging Neurosci.

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Prion-like seeded misfolding of host proteins is the leading hypothesised cause of neurodegenerative diseases. The exploitation of the mechanism in the protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays have transformed prion disease research and diagnosis and have steadily become more widely used for research into other neurodegenerative disorders. Clinical trials in adult neurodegenerative diseases have been expensive, slow, and disappointing in terms of clinical benefits. There are various possible factors contributing to the failure to identify disease-modifying treatments for adult neurodegenerative diseases, some of which include: limited accuracy of antemortem clinical diagnosis resulting in the inclusion of patients with the “incorrect” pathology for the therapeutic; the role of co-pathologies in neurodegeneration rendering treatments targeting one pathology alone ineffective; treatment of the primary neurodegenerative process too late, after irreversible secondary processes of neurodegeneration have become established or neuronal loss is already extensive; and preclinical models used to develop treatments not accurately representing human disease. The use of seed amplification assays in clinical trials offers an opportunity to tackle these problems by sensitively detecting in vivo the proteopathic seeds thought to be central to the biology of neurodegenerative diseases, enabling improved diagnostic accuracy of the main pathology and co-pathologies, and very early intervention, particularly in patients at risk of monogenic forms of neurodegeneration. The possibility of quantifying proteopathic seed load, and its reduction by treatments, is an attractive pharmacodynamic biomarker in the preclinical and early clinical stages of drug development. Here we review some potential applications of seed amplification assays in clinical trials.

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“…Subsequently, multiple teams have observed high specificity and sensitivity of α-Syn RT-QuIC in CSF and brain tissue ( Groveman et al, 2018 ; Sano et al, 2018 ; Bongianni et al, 2019 ; Garrido et al, 2019 ; Kang et al, 2019 ; van Rumund et al, 2019 ; Han et al, 2020 ; Rossi et al, 2020 ; Bargar et al, 2021b ; Brockmann et al, 2021 ; Iranzo et al, 2021 ; Perra et al, 2021 ; Poggiolini et al, 2021 ). Recent studies applied RT-QuIC to submandibular gland, biopsies of skin, and olfactory mucosa, which indicates a growing trend toward non-invasive testing ( De Luca et al, 2019 ; Manne et al, 2020a , b ; Wang et al, 2020 ; Bargar et al, 2021a ; Kuzkina et al, 2021 ; Stefani et al, 2021 ; Luan et al, 2022 ). The results of protease resistance of RT-QuIC products showed that seeded fibrils had obvious disease-specific protease sensitivity in PD and MSA, indicating that RT-QuIC amplification could preserve the structural features of the initial seeds and help to differentiate between different strains ( Manne et al, 2020b ).…”

Section: Techniques Available To Detect α-Syn Seedingmentioning

confidence: 99%

Clinical application of prion-like seeding in α-synucleinopathies: Early and non-invasive diagnosis and therapeutic development

Luo

Zheng

et al. 2022

Front. Mol. Neurosci.

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The accumulation and deposition of misfolded α-synuclein (α-Syn) aggregates in the brain is the central event in the pathogenesis of α-synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple-system atrophy. Currently, the diagnosis of these diseases mainly relies on the recognition of advanced clinical manifestations. Differential diagnosis among the various α-synucleinopathies subtypes remains challenging. Misfolded α-Syn can template its native counterpart into the same misfolded one within or between cells, behaving as a prion-like seeding. Protein-misfolding cyclic amplification and real-time quaking-induced conversion are ultrasensitive protein amplification assays initially used for the detection of prion diseases. Both assays showed high sensitivity and specificity in detection of α-synucleinopathies even in the pre-clinical stage recently. Herein, we collectively reviewed the prion-like properties of α-Syn and critically assessed the detection techniques of α-Syn-seeding activity. The progress of test tissues, which tend to be less invasive, is presented, particularly nasal swab, which is now widely known owing to the global fight against coronavirus disease 2019. We highlight the clinical application of α-Syn seeding in early and non-invasive diagnosis. Moreover, some promising therapeutic perspectives and clinical trials targeting α-Syn-seeding mechanisms are presented.

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Diagnostic Value of Salivary Real‐Time Quaking‐Induced Conversion in Parkinson's Disease and Multiple System Atrophy

Cited by 53 publications

References 17 publications

α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

The Future of Seed Amplification Assays and Clinical Trials

Clinical application of prion-like seeding in α-synucleinopathies: Early and non-invasive diagnosis and therapeutic development

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