scholarly journals Clinical Use of Improved Diagnostic Testing for Detection of Prion Disease

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 789
Author(s):  
Mark P. Figgie ◽  
Brian S. Appleby
Keyword(s):  
Diagnostic Accuracy ◽  
Prion Disease ◽  
Clinical Utility ◽  
Prion Diseases ◽  
Diagnostic Testing ◽  
High Sensitivity ◽  
Clinical Use ◽  
Laboratory Markers ◽  
Disease Subtypes ◽  
Prognostic Data

Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until late in the disease course. Additionally, many commonly used laboratory markers are non-specific to prion disease. The recent introduction of second-generation real time quaking induced conversion (RT-QuIC) has revolutionized pre-mortem diagnosis of prion disease due to its extremely high sensitivity and specificity. However, RT-QuIC does not provide prognostic data and has decreased diagnostic accuracy in some rarer, atypical prion diseases. The objective of this review is to provide an overview of the current clinical utility of fluid-based biomarkers, neurodiagnostic testing, and brain imaging in the diagnosis of prion disease and to suggest guidelines for their clinical use, with a focus on rarer prion diseases with atypical features. Recent advancements in laboratory-based testing and imaging criteria have shown improved diagnostic accuracy and prognostic potential in prion disease, but because these diagnostic tests are not sensitive in some prion disease subtypes and diagnostic test sensitivities are unknown in the event that CWD transmits to humans, it is important to continue investigations into the clinical utility of various testing modalities.

scholarly journals Molecular Characterization of the Danish Prion Diseases Cohort With Special Emphasis on Rare and Unique Cases

2019 ◽  
Vol 78 (11) ◽  
pp. 980-992 ◽  
Author(s):  
Aušrinė Areškevičiūtė ◽  
Helle Broholm ◽  
Linea C Melchior ◽  
Anna Bartoletti-Stella ◽  
Piero Parchi ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Prion Disease ◽  
Prion Diseases ◽  
The Past ◽  
Disease Biology ◽  
Fresh Frozen ◽  
Jakob Disease ◽  
Disease Subtypes ◽  
Codon 129

Abstract The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology.

scholarly journals Beyond Diagnostic Accuracy: The Clinical Utility of Diagnostic Tests

2012 ◽  
Vol 58 (12) ◽  
pp. 1636-1643 ◽  
Author(s):  
Patrick MM Bossuyt ◽  
Johannes B Reitsma ◽  
Kristian Linnet ◽  
Karel GM Moons
Keyword(s):  
Diagnostic Accuracy ◽  
Diagnostic Tests ◽  
Clinical Utility ◽  
Randomized Clinical Trials ◽  
Diagnostic Testing ◽  
Daily Practice ◽  
Technical Performance ◽  
Management Actions ◽  
Negative Results ◽  
Definition Of

Abstract Like any other medical technology or intervention, diagnostic tests should be thoroughly evaluated before their introduction into daily practice. Increasingly, decision makers, physicians, and other users of diagnostic tests request more than simple measures of a test's analytical or technical performance and diagnostic accuracy; they would also like to see testing lead to health benefits. In this last article of our series, we introduce the notion of clinical utility, which expresses—preferably in a quantitative form—to what extent diagnostic testing improves health outcomes relative to the current best alternative, which could be some other form of testing or no testing at all. In most cases, diagnostic tests improve patient outcomes by providing information that can be used to identify patients who will benefit from helpful downstream management actions, such as effective treatment in individuals with positive test results and no treatment for those with negative results. We describe how comparative randomized clinical trials can be used to estimate clinical utility. We contrast the definition of clinical utility with that of the personal utility of tests and markers. We show how diagnostic accuracy can be linked to clinical utility through an appropriate definition of the target condition in diagnostic-accuracy studies.

scholarly journals The Clinical Utility of the Heparin Neutralization Assay in the Diagnosis of Heparin-Induced Thrombocytopenia

2017 ◽  
Vol 24 (5) ◽  
pp. 749-754 ◽  
Author(s):  
Gang Zheng ◽  
Michael B. Streiff ◽  
Clifford M. Takemoto ◽  
Jennifer Bynum ◽  
Elise Gelwan ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Predictive Value ◽  
Clinical Utility ◽  
Predictive Accuracy ◽  
High Sensitivity ◽  
Neutralization Assay ◽  
Serotonin Release ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heparin Induced Thrombocytopenia ◽  
Heparin Neutralization

Heparin-induced thrombocytopenia (HIT) remains diagnostically challenging. Immunoassays including PF4/heparin enzyme-linked immunosorbent assay (ELISA) have high sensitivity but low specificity. Whether the heparin neutralization assay (HNA) improves the diagnostic accuracy of the PF4/heparin ELISA for HIT is uncertain. In this study, to assess its clinical utility and evaluate whether it improves the diagnostic accuracy for HIT, we implemented HNA in conjunction with PF4/heparin ELISA over a 1-year period. A total of 1194 patient samples were submitted to the laboratory for testing from December 2015 to November 2016. Heparin neutralization assay alone is a poor predictor for HIT, but it has high negative predictive value (NPV): Cases with %inhibition <70% are always negative for serotonin release assay. It improves the diagnostic positive predictive value (PPV) of ELISA without compromising sensitivity: ELISA optical density (OD) ≥1.4 alone has a sensitivity of 88% (14/16) and a PPV of 61% (14/23); with HNA %inhibition ≥70%, the sensitivity remains 88% (14/16) and PPV is 82% (14/17). 4Ts score correlates with ELISA OD and predicts HIT; the predictive accuracy of 4Ts score is further improved by HNA. Interestingly, HNA %inhibition of <70% correlates with low 4Ts scores. Based on its high NPV, HNA has the potential to facilitate more timely and accurate HIT diagnosis.

scholarly journals Diagnosis of prion diseases by RT-QuIC results in improved surveillance

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e1017-e1026 ◽  
Author(s):  
Daniel D. Rhoads ◽  
Aleksandra Wrona ◽  
Aaron Foutz ◽  
Janis Blevins ◽  
Kathleen Glisic ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Prion Disease ◽  
Disease Surveillance ◽  
Prion Diseases ◽  
False Negative ◽  
High Sensitivity ◽  
Disease Type ◽  
Diagnostic Sensitivity ◽  
Class Iii ◽  
The Impact

ObjectiveTo present the National Prion Disease Pathology Surveillance Center's (NPDPSC’s) experience using CSF real-time quaking-induced conversion (RT-QuIC) as a diagnostic test, to examine factors associated with false-negative RT-QuIC results, and to investigate the impact of RT-QuICs on prion disease surveillance.MethodsBetween May 2015 and April 2018, the NPDPSC received 10,498 CSF specimens that were included in the study. Sensitivity and specificity analyses were performed on 567 autopsy-verified cases. Prion disease type, demographic characteristics, specimen color, and time variables were examined for association with RT-QuIC results. The effect of including positive RT-QuIC cases in prion disease surveillance was examined.ResultsThe diagnostic sensitivity and specificity of RT-QuIC across all prion diseases were 90.3% and 98.5%, respectively. Diagnostic sensitivity was lower for fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, sporadic fatal insomnia, variably protease sensitive prionopathy, and the VV1 and MM2 subtypes of sporadic Creutzfeldt-Jakob disease. Individuals with prion disease and negative RT-QuIC results were younger and had lower tau levels and nonelevated 14-3-3 levels compared to RT-QuIC–positive cases. Sensitivity was high throughout the disease course. Some cases that initially tested RT-QuIC negative had a subsequent specimen test positive. Including positive RT-QuIC cases in surveillance statistics increased laboratory-based case ascertainment of prion disease by 90% over autopsy alone.ConclusionsRT-QuIC has high sensitivity and specificity for diagnosing prion diseases. Sensitivity limitations are associated with prion disease type, age, and related CSF diagnostic results. RT-QuIC greatly improves laboratory-based prion disease ascertainment for surveillance purposes.Classification of evidenceThis study provides Class III evidence that second-generation RT-QuIC identifies prion disease with a sensitivity of 90.3% and specificity of 98.5% among patients being screened for these diseases due to concerning symptoms.

Features of Thrombi and Diagnostic Accuracy of Impedance Plethysmography in Symptomatic and Asymptomatic Deep Vein Thrombosis

1993 ◽  
Vol 70 (02) ◽  
pp. 266-269 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Benilde Cosmi ◽  
Stefano Radicchia ◽  
Franca Veschi ◽  
Enrico Boschetti ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Diagnostic Accuracy ◽  
High Sensitivity ◽  
Impedance Plethysmography ◽  
Surveillance Programme ◽  
Vein Thrombosis ◽  
Asymptomatic Patients ◽  
High Prevalence ◽  
The Mean ◽  
Deep Vein

SummaryImpedance plethysmography (IPG) has high sensitivity and specificity in patients with symptomatic deep vein thrombosis (DVT) while it fails to detect asymptomatic DVT. The aim of this study was to determine whether the features of thrombi such as location, size and occlusiveness could explain the different accuracy of IPG in symptomatic and asymptomatic DVT patients. One-hundred and seventeen consecutive outpatients with a clinical suspicion of DVT and 246 consecutive patients undergoing hip surgery were admitted to the study. In symptomatic patients IPG was performed on the day of referral, followed by venography, while in asymptomatic patients IPG was performed as a surveillance programme, followed by bilateral venography.A venography proved DVT was observed in 37% of the symptomatic patients and 34% of the asymptomatic limbs. A significantly higher proportion of proximal DVTs was found in symptomatic patients than in asymptomatic patients (78% vs 46%; p = 0.001). The mean Marder score, taken as an index of thrombus size, was significantly higher in symptomatic patients than in asymptomatic patients (19.0 vs 9.6; p = 0.0001). A significantly higher proportion of occlusive DVTs was observed in symptomatic than in asymptomatic patients (69% vs 36%; p = 0.001).We conclude that the unsatisfactory diagnostic accuracy of IPG in asymptomatic DVT is due to the high prevalence of distal, small and non occlusive thrombi. Such thrombi are unlikely to cause a critical obstruction of the venous outflow and therefore to produce a positive IPG.

scholarly journals A novel 8.7-kb mitochondrial genome deletion accurately detects endometriosis in the plasma of symptomatic women

2020 ◽  
Vol 14 (2) ◽  
pp. 97-107
Author(s):  
Andrew Harbottle ◽  
Andrea Maggrah ◽  
Robert Usher ◽  
Elise Desa ◽  
Jennifer M Creed
Keyword(s):  
Diagnostic Accuracy ◽  
Case Control ◽  
Menstrual Phase ◽  
Pcr Assay ◽  
Potential Biomarker ◽  
Significant Difference ◽  
Mtdna Deletion ◽  
Disease Subtypes ◽  
Improve Patient Management ◽  
Improve Patient

Aim: To evaluate an 8.7-kb mitochondrial DNA (mtDNA) deletion as a potential biomarker of endometriosis. Materials & methods: We tested the diagnostic accuracy of the 8.7-kb deletion real-time PCR assay using 182 prospectively collected blood samples from females presenting with symptoms of endometriosis in a case–control format. Results: The assay differentiated between endometriosis and controls (area under curve: 0.74–0.89) with a statistically significant difference (p < 0.05) in 8.7-kb deletion levels measured for all disease subtypes and stages. No correlation was seen between 8.7-kb deletion levels and participant or specimen age, hormone status or menstrual phase. Conclusion: The diagnostic accuracy of the 8.7-kb deletion for endometriosis suggests potential utility in the clinic to improve patient management.

scholarly journals Deep learning systems detect dysplasia with human-like accuracy using histopathology and probe-based confocal laser endomicroscopy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shan Guleria ◽  
Tilak U. Shah ◽  
J. Vincent Pulido ◽  
Matthew Fasullo ◽  
Lubaina Ehsan ◽  
...  
Keyword(s):  
Deep Learning ◽  
Diagnostic Accuracy ◽  
High Sensitivity ◽  
Confocal Laser Endomicroscopy ◽  
Confocal Laser ◽  
Learning Approaches ◽  
Learning Models ◽  
Whole Slide Image ◽  
Slide Image ◽  
Level Model

AbstractProbe-based confocal laser endomicroscopy (pCLE) allows for real-time diagnosis of dysplasia and cancer in Barrett’s esophagus (BE) but is limited by low sensitivity. Even the gold standard of histopathology is hindered by poor agreement between pathologists. We deployed deep-learning-based image and video analysis in order to improve diagnostic accuracy of pCLE videos and biopsy images. Blinded experts categorized biopsies and pCLE videos as squamous, non-dysplastic BE, or dysplasia/cancer, and deep learning models were trained to classify the data into these three categories. Biopsy classification was conducted using two distinct approaches—a patch-level model and a whole-slide-image-level model. Gradient-weighted class activation maps (Grad-CAMs) were extracted from pCLE and biopsy models in order to determine tissue structures deemed relevant by the models. 1970 pCLE videos, 897,931 biopsy patches, and 387 whole-slide images were used to train, test, and validate the models. In pCLE analysis, models achieved a high sensitivity for dysplasia (71%) and an overall accuracy of 90% for all classes. For biopsies at the patch level, the model achieved a sensitivity of 72% for dysplasia and an overall accuracy of 90%. The whole-slide-image-level model achieved a sensitivity of 90% for dysplasia and 94% overall accuracy. Grad-CAMs for all models showed activation in medically relevant tissue regions. Our deep learning models achieved high diagnostic accuracy for both pCLE-based and histopathologic diagnosis of esophageal dysplasia and its precursors, similar to human accuracy in prior studies. These machine learning approaches may improve accuracy and efficiency of current screening protocols.

scholarly journals Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

2021 ◽  
Author(s):  
Marina Betancor ◽  
Laura Moreno-Martínez ◽  
Óscar López-Pérez ◽  
Alicia Otero ◽  
Adelaida Hernaiz ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Prion Disease ◽  
Tetanus Toxin ◽  
Neuronal Survival ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Murine Models ◽  
Terminal Fragment ◽  
Lateral Sclerosis

AbstractThe non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

scholarly journals Detection of Prions in Brain Homogenates and CSF Samples Using a Second-Generation RT-QuIC Assay: A Useful Tool for Retrospective Analysis of Archived Samples

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 750
Author(s):  
Tibor Moško ◽  
Soňa Galušková ◽  
Radoslav Matěj ◽  
Magdalena Brůžová ◽  
Karel Holada
Keyword(s):  
Retrospective Analysis ◽  
Prion Disease ◽  
Second Generation ◽  
Prion Diseases ◽  
Neuropsychiatric Symptoms ◽  
Final Diagnosis ◽  
Post Mortem ◽  
Long Term Storage ◽  
Archived Samples

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.

scholarly journals Deletion of Kif5c Does Not Alter Prion Disease Tempo or Spread in Mouse Brain

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1391
Author(s):  
Brent Race ◽  
Katie Williams ◽  
Chase Baune ◽  
James F. Striebel ◽  
Clayton W. Winkler ◽  
...  
Keyword(s):  
Prion Disease ◽  
Molecular Motors ◽  
Prion Diseases ◽  
Mouse Strains ◽  
Survival Times ◽  
Knock Out ◽  
Transport Vesicles ◽  
The Central Nervous System ◽  
Knock Out Mice ◽  
Scrapie Strains

In prion diseases, the spread of infectious prions (PrPSc) is thought to occur within nerves and across synapses of the central nervous system (CNS). However, the mechanisms by which PrPSc moves within axons and across nerve synapses remain undetermined. Molecular motors, including kinesins and dyneins, transport many types of intracellular cargo. Kinesin-1C (KIF5C) has been shown to transport vesicles carrying the normal prion protein (PrPC) within axons, but whether KIF5C is involved in PrPSc axonal transport is unknown. The current study tested whether stereotactic inoculation in the striatum of KIF5C knock-out mice (Kif5c−/−) with 0.5 µL volumes of mouse-adapted scrapie strains 22 L or ME7 would result in an altered rate of prion spreading and/or disease timing. Groups of mice injected with each strain were euthanized at either pre-clinical time points or following the development of prion disease. Immunohistochemistry for PrP was performed on brain sections and PrPSc distribution and tempo of spread were compared between mouse strains. In these experiments, no differences in PrPSc spread, distribution or survival times were observed between C57BL/6 and Kif5c−/− mice.

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