Abstract:Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal and potentially transmissible neurodegenerative disease caused by misfolded prion proteins. To date, effective therapeutics are not available and accurate diagnosis can be challenging. Clinical diagnostic criteria employ a combination of characteristic cerebrospinal fluid (CSF) 14-3-3 proteins, MRI findings, EEG changes, and neuropsychiatric symptoms. Supportive biomarkers such as high CSF total Tau may aid the diagnostic process. However, discordant results… Show more
“…Misfolded prion protein (PrP Sc ) represents the only specific TSE marker, and its detection is used for final confirmation of the disease by immunohistochemistry and western blot in post-mortem brain samples. Clinical diagnosis of TSEs is based mainly on characteristic neuropsychiatric symptoms, supported by results of EEG tests, MRI scans, and diagnostic biomarkers, such as the level of 14-3-3 and total Tau protein in CSF [3]. The ante-mortem options for direct detection of prions are limited, due to low levels of PrP Sc in peripheral tissues.…”
The possibilities for diagnosing prion diseases have shifted significantly over the last 10 years. The RT-QuIC assay option has been added for neuropsychiatric symptoms, supporting biomarkers and final post-mortem confirmation. Samples of brain homogenates used for final diagnosis, archived for many years, provide the possibility for retrospective studies. We used a second-generation RT-QuIC assay to detect seeding activity in different types of sporadic and genetic prion diseases in archival brain homogenates and post-mortem CSF samples that were 2 to 15 years old. Together, we tested 92 archival brain homogenates: 39 with definite prion disease, 28 with definite other neurological disease, and 25 with no signs of neurological disorders. The sensitivity and specificity of the assay were 97.4% and 100%, respectively. Differences were observed in gCJD E200K, compared to the sporadic CJD group. In 52 post-mortem CSF samples—24 with definite prion disease and 28 controls—we detected the inhibition of seeding reaction due to high protein content. Diluting the samples eliminated such inhibition and led to 95.8% sensitivity and 100% specificity of the assay. In conclusion, we proved the reliability of archived brain homogenates and post-mortem CSF samples for retrospective analysis by RT-QuIC after long-term storage, without changed reactivity.
“…Misfolded prion protein (PrP Sc ) represents the only specific TSE marker, and its detection is used for final confirmation of the disease by immunohistochemistry and western blot in post-mortem brain samples. Clinical diagnosis of TSEs is based mainly on characteristic neuropsychiatric symptoms, supported by results of EEG tests, MRI scans, and diagnostic biomarkers, such as the level of 14-3-3 and total Tau protein in CSF [3]. The ante-mortem options for direct detection of prions are limited, due to low levels of PrP Sc in peripheral tissues.…”
The possibilities for diagnosing prion diseases have shifted significantly over the last 10 years. The RT-QuIC assay option has been added for neuropsychiatric symptoms, supporting biomarkers and final post-mortem confirmation. Samples of brain homogenates used for final diagnosis, archived for many years, provide the possibility for retrospective studies. We used a second-generation RT-QuIC assay to detect seeding activity in different types of sporadic and genetic prion diseases in archival brain homogenates and post-mortem CSF samples that were 2 to 15 years old. Together, we tested 92 archival brain homogenates: 39 with definite prion disease, 28 with definite other neurological disease, and 25 with no signs of neurological disorders. The sensitivity and specificity of the assay were 97.4% and 100%, respectively. Differences were observed in gCJD E200K, compared to the sporadic CJD group. In 52 post-mortem CSF samples—24 with definite prion disease and 28 controls—we detected the inhibition of seeding reaction due to high protein content. Diluting the samples eliminated such inhibition and led to 95.8% sensitivity and 100% specificity of the assay. In conclusion, we proved the reliability of archived brain homogenates and post-mortem CSF samples for retrospective analysis by RT-QuIC after long-term storage, without changed reactivity.
“… PSG Reduction in sleep spindles, K-complexes, slow-wave sleep, REM sleep, and total sleep time 6 No reports were found in PubMed. No reports were found in PubMed Abnormal sleep architecture, sleep inefficiency, Reduction in sleep spindles, K-complexes, N3 sleep and REM sleep absence, sleep apnea hypoventilation, periodic leg movements CSF biomarkers Sensitivity of RT-QuIC was 100%, 19 specificity of RT-QuIC was 99–100% 18 Sensitivity of RT-QuIC was 100%, 19 specificity of RT-QuIC was 99–100%. 18 Sensitivity of RT-QuIC was 96.8%, 19 specificity of RT-QuIC was 99–100%.…”
Section: Discussionmentioning
confidence: 99%
“… Figure 4 Positive skin biopsy tissue ( A ) and CSF samples ( B ) RT-QuIC results at four months after onset (Updated diagnostic guidelines for sCJD have incorporated RT-QuIC for early diagnosis of disease, surveillance, evaluation of PrP sc inoculation in different tissues, and in trial monitoring). 18 …”
Creutzfeldt–Jakob disease (CJD) subtypes are difficult to identify due to the heterogeneity of the clinical phenotype, and early accurate identification of sporadic CJD (sCJD) subtypes aids prognosis prediction. Currently, the diagnosis of sCJD subtypes is mainly based on brain tissue biopsy or autopsy. In this report, we present a case of confirmed sCJD initially presenting as insomnia. We described detailed information including clinical, electroencephalographic, polysomnographic, positron emission tomography-computed tomographic and other neuroimaging findings, cerebrospinal fluid biomarkers, skin tissue biopsy and whole blood
PRNP
gene sequencing in this patient. An extensive literature search was performed in order to better understand the diagnosis of various sCJD subtypes, particularly the thalamic form, sCJDMM2 (also known as sporadic fatal insomnia). Our study highlights sporadic fatal insomnia as a differential diagnosis of sCJD.
“…For instance, atypical parkinsonism, characterized by motor symptoms derived from au misfolding and aggregation, have been accurately differentiated from synucleinopathies according to real-time quaking-induced conversion results [234]. Along with kinetic analyses, improvements in antibody-mediated detection of specific conformation are paving the way for the usage of a combination ratio of aggregation-related and neuronal damage proteins as diagnostic biomarkers [242][243][244]. On the other side, anti-amyloidogenic compounds are being studied as potential therapeutics [245][246][247].…”
Section: Clinical Outlook and Concluding Remarksmentioning
Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.
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