Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study

Kuzkina, Anastasia; Bargar, Connor; Schmitt, Daniela; Rößle, Jonas; Wang, Wen; Schubert, Anna‐Lena; Tatsuoka, Curtis; Gunzler, Steven A.; Zou, Wen-Quan; Volkmann, Jens; Sommer, Claudia; Doppler, Kathrin; Chen, Shu G.

doi:10.1038/s41531-021-00242-2

Cited by 70 publications

(68 citation statements)

References 49 publications

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“…Heterogeneity of the prion-like seeding activity has also been reported, depending on the α-syn strain [ 228 , 286 , 314 ]. Similar to the case of tauopathy, abnormal α-syn in brain, CSF and skin samples derived from patients with synucleinopathies have been shown to be specifically detected by PMCA and RT-QuIC methods and to be useful biomarkers in the early stages of synucleinopathies [ 88 , 174 , 245 , 256 , 264 ]. PMCA analysis using brain samples and CSF derived from synucleinopathy cases has revealed differences in the seeding activity of α-syn derived from PD cases (PD-syn) and MSA-syn [ 263 ].…”

Section: Experimental Prion-like Amplification and Transmission Of Pa...mentioning

confidence: 99%

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

et al. 2022

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Intracellular accumulation of abnormal proteins with conformational changes is the defining neuropathological feature of neurodegenerative diseases. The pathogenic proteins that accumulate in patients' brains adopt an amyloid-like fibrous structure and exhibit various ultrastructural features. The biochemical analysis of pathogenic proteins in sarkosyl-insoluble fractions extracted from patients’ brains also shows disease-specific features. Intriguingly, these ultrastructural and biochemical features are common within the same disease group. These differences among the pathogenic proteins extracted from patients’ brains have important implications for definitive diagnosis of the disease, and also suggest the existence of pathogenic protein strains that contribute to the heterogeneity of pathogenesis in neurodegenerative diseases. Recent experimental evidence has shown that prion-like propagation of these pathogenic proteins from host cells to recipient cells underlies the onset and progression of neurodegenerative diseases. The reproduction of the pathological features that characterize each disease in cellular and animal models of prion-like propagation also implies that the structural differences in the pathogenic proteins are inherited in a prion-like manner. In this review, we summarize the ultrastructural and biochemical features of pathogenic proteins extracted from the brains of patients with neurodegenerative diseases that accumulate abnormal forms of tau, α-synuclein, and TDP-43, and we discuss how these disease-specific properties are maintained in the brain, based on recent experimental insights.

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Section: Experimental Prion-like Amplification and Transmission Of Pa...mentioning

confidence: 99%

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

et al. 2022

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“…Although case numbers in this study are relatively limited that makes us hesitant to address the diagnostic accuracy of the established α-Syn RT-QuIC, positive in all 5 brain and 13 skin samples of PD and negative in all controls of other diseases propose a significant potential in the future usage. Higher diagnostic accuracies (over 90%) of α-Syn RT-QuIC for α-synucleinopathy have been reported in some previous studies with relatively large case numbers (Bargar et al, 2021;Donadio et al, 2021;Kuzkina et al, 2021;Mammana et al, 2021). High accuracies of PD diagnosis are obtained not only from skin tissues but also from many other CNS and peripheral tissues, such as brains, CSF, salivary gland, and colon (Bargar et al, 2021).…”

Section: Discussionmentioning

confidence: 80%

“…Immunoassays for α-Syn, both total and phosphorylated, in cerebrospinal fluid (CSF) and other peripheral tissues of PD and DLB have been widely evaluated for diagnostic purpose, but with wide variations (Gelpi et al, 2014;Donadio et al, 2017a;Eusebi et al, 2017;Kalia, 2019). More recently, a realtime quaking-induced conversion (RT-QuIC) using recombinant α-Syn as substrate has been developed and applied in detecting miniscule quantities of abnormal α-Syn in various tissues and body fluids of α-synucleinopathy, particularly in skin specimen, revealing a promising diagnostic value (Fairfoul et al, 2016;Bargar et al, 2021;Donadio et al, 2021;Kuzkina et al, 2021;Mammana et al, 2021;Rossi et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Application of α-Syn Real-Time Quaking-Induced Conversion for Brain and Skin Specimens of the Chinese Patients With Parkinson’s Disease

Chen

Jiao²,

Huang³

et al. 2022

Front. Aging Neurosci.

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The real-time quaking-induced conversion (RT-QuIC) assay has been developed and used as an in vitro diagnostic tool for Parkinson’s disease (PD). In this study, we established α-Syn RT-QuIC using recombinant human α-Syn as the substrate. All 5 brain homogenates of neuropathological PD cases and 13 skin homogenates of clinical PD cases showed positive results, whereas all the samples of negative controls remain negative. Meantime, randomly selected 6 skin samples of PD cases and 6 skin samples of sCJD cases showed negative in opposite prion RT-QuIC and α-Syn RT-QuIC. Our α-Syn RT-QuIC showed dose-dependent manner between the lag times and peak ThT fluorescent values. Additionally, the detecting limitation was about 10–7 dilution for brain tissues and 10–6 for skins. Those data indicate a reliable specificity and good sensitivity of the established α-Syn RT-QuIC in identifying and amplifying the misfolded α-Syn in brain and skin tissues of patients with PD.

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“…The asyn SAA assay has been successfully employed to detect and amplify asyn seeds from a range of different biological samples. Though CSF has been most studied (Fairfoul et al, 2016 ; Shahnawaz et al, 2017 , 2020 ; Groveman et al, 2018 ; Kang et al, 2019 ; Poggiolini et al, 2022 ), extracts of brain (Groveman et al, 2018 ; Bargar et al, 2021 ), skin (Wang et al, 2020b ; Kuzkina et al, 2021 ), olfactory mucosa (De Luca et al, 2019 ), submandibular glands (Manne et al, 2020 ) and gut (Fenyi et al, 2019 ) have all been utilized to differentiate PD patients from other synucleinopathies and controls. Although there is currently no universal protocol, reports have shown high sensitivity and specificity of the assay with differing experimental conditions.…”

Section: Asyn Amplification Assay To Identify Different Strainsmentioning

confidence: 99%

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

Just

Gram

Theologidis

et al. 2022

Front. Aging Neurosci.

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Pathogenic alpha-synuclein (asyn) aggregates are a defining feature of neurodegenerative synucleinopathies, which include Parkinson's disease, Lewy body dementia, pure autonomic failure and multiple system atrophy. Early accurate differentiation between these synucleinopathies is challenging due to the highly heterogeneous clinical profile at early prodromal disease stages. Therefore, diagnosis is often made in late disease stages when a patient presents with a broad range of motor and non-motor symptoms easing the differentiation. Increasing data suggest the clinical heterogeneity seen in patients is explained by the presence of distinct asyn strains, which exhibit variable morphologies and pathological functions. Recently, asyn seed amplification assays (PMCA and RT-QuIC) and conformation-specific ligand assays have made promising progress in differentiating between synucleinopathies in prodromal and advanced disease stages. Importantly, the cellular environment is known to impact strain morphology. And, asyn aggregate pathology can propagate trans-synaptically along the brain-body axis, affecting multiple organs and propagating through multiple cell types. Here, we present our hypothesis that the changing cellular environments, an asyn seed may encounter during its brain-to-body or body-to-brain propagation, may influence the structure and thereby the function of the aggregate strains developing within the different cells. Additionally, we aim to review strain characteristics of the different synucleinopathies in clinical and preclinical studies. Future preclinical animal models of synucleinopathies should investigate if asyn strain morphology is altered during brain-to-body and body-to-brain spreading using these seeding amplification and conformation-specific assays. Such findings would greatly deepen our understanding of synucleinopathies and the potential link between strain and phenotypic variability, which may enable specific diagnosis of different synucleinopathies in the prodromal phase, creating a large therapeutic window with potential future applications in clinical trials and personalized therapeutics.

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Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study

Cited by 70 publications

References 49 publications

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

Application of α-Syn Real-Time Quaking-Induced Conversion for Brain and Skin Specimens of the Chinese Patients With Parkinson’s Disease

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

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