Publications by authors named "Matthias Schmitz"

93 Publications

Prion protein oligomers cause neuronal cytoskeletal damage in rapidly progressive Alzheimer's disease.

Mol Neurodegener 2021 02 22;16(1):11. Epub 2021 Feb 22.

Department of Neurology, University Medicine Goettingen and German Center for Neurodegenerative Diseases (DZNE), 37075, Goettingen, Germany.

Background: High-density oligomers of the prion protein (HDPs) have previously been identified in brain tissues of patients with rapidly progressive Alzheimer's disease (rpAD). The current investigation aims at identifying interacting partners of HDPs in the rpAD brains to unravel the pathological involvement of HDPs in the rapid progression.

Methods: HDPs from the frontal cortex tissues of rpAD brains were isolated using sucrose density gradient centrifugation. Proteins interacting with HDPs were identified by co-immunoprecipitation coupled with mass spectrometry. Further verifications were carried out using proteomic tools, immunoblotting, and confocal laser scanning microscopy.

Results: We identified rpAD-specific HDP-interactors, including the growth arrest specific 2-like 2 protein (G2L2). Intriguingly, rpAD-specific disturbances were found in the localization of G2L2 and its associated proteins i.e., the end binding protein 1, α-tubulin, and β-actin.

Discussion: The results show the involvement of HDPs in the destabilization of the neuronal actin/tubulin infrastructure. We consider this disturbance to be a contributing factor for the rapid progression in rpAD.
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http://dx.doi.org/10.1186/s13024-021-00422-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898440PMC
February 2021

Altered mRNA and Protein Expression of Monocarboxylate Transporter MCT1 in the Cerebral Cortex and Cerebellum of Prion Protein Knockout Mice.

Int J Mol Sci 2021 Feb 4;22(4). Epub 2021 Feb 4.

Département de Physiologie, Université de Lausanne, 1005 Lausanne, Switzerland.

The effect of a cellular prion protein (PrP) deficiency on neuroenergetics was primarily analyzed via surveying the expression of genes specifically involved in lactate/pyruvate metabolism, such as monocarboxylate transporters (, , ). The aim of the present study was to elucidate a potential involvement of PrP in the regulation of energy metabolism in different brain regions. By using quantitative real-time polymerase chain reaction (qRT-PCR), we observed a marked reduction in MCT1 mRNA expression in the cortex of symptomatic Zürich I mice, as compared to their wild-type (WT) counterparts. MCT1 downregulation in the cortex was accompanied with significantly decreased expression of the MCT1 functional interplayer, the Na/K ATPase α2 subunit. Conversely, the MCT1 mRNA level was significantly raised in the cerebellum of vs. WT control group, without a substantial change in the Na/K ATPase α2 subunit expression. To validate the observed mRNA findings, we confirmed the observed change in MCT1 mRNA expression level in the cortex at the protein level. MCT4, highly expressed in tissues that rely on glycolysis as an energy source, exhibited a significant reduction in the hippocampus of vs. WT mice. The present study demonstrates that a lack of PrP leads to altered MCT1 and MCT4 mRNA/protein expression in different brain regions of vs. WT mice. Our findings provide evidence that PrP might affect the monocarboxylate intercellular transport, which needs to be confirmed in further studies.
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http://dx.doi.org/10.3390/ijms22041566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913939PMC
February 2021

Optimization of the Real-Time Quaking-Induced Conversion Assay for Prion Disease Diagnosis.

Front Bioeng Biotechnol 2020 19;8:586890. Epub 2020 Nov 19.

Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), University Medical Center Göttingen, Göttingen, Germany.

The real-time quaking-induced conversion (RT-QuIC) assay is a highly reproducible and robust methodology exhibiting an excellent pre-mortem diagnostic accuracy for prion diseases. However, the protocols might be time-consuming and improvement of the detection technology is needed. In the present study, we investigated the influence of a pre-analytical cerebrospinal fluid (CSF) treatment with proteinase K (PK) on the kinetic of the RT-QuIC signal response. For this purpose, we added PK at different concentrations in RT-QuIC reactions seeded with Creutzfeldt-Jakob disease (sCJD) CSF. We observed that a mild pre-analytical PK treatment of CSF samples resulted in an increased seeding efficiency of the RT-QuIC reaction. Quantitative seeding parameters, such as a higher area under the curve (AUC) value or a shorter lag phase indicated a higher conversion efficiency after treatment. The diagnostic accuracy resulting from 2 μg/ml PK treatment was analyzed in a retrospective study, where we obtained a sensitivity of 89%. Additionally, we analyzed the agreement with the previously established standard RT-QuIC protocol without PK treatment in a prospective study. Here, we found an overall agreement of 94% to 96%. A Cohen's kappa of 0.9036 (95% CI: 0.8114-0.9958) indicates an almost perfect agreement between both protocols. In conclusion, the outcome of our study can be used for a further optimization of the RT-QuIC assay in particular for a reduction of the testing time.
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http://dx.doi.org/10.3389/fbioe.2020.586890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710546PMC
November 2020

A prognostic model for overall survival in sporadic Creutzfeldt-Jakob disease.

Alzheimers Dement 2020 10 2;16(10):1438-1447. Epub 2020 Jul 2.

Department of Neurology, University Medical School, Göttingen, Germany.

Introduction: We developed a prognostic model for overall survival after diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) using data from a German surveillance study.

Methods: We included 1226 sCJD cases (median age 66 years, range 19-89 years; 56.8% women with information on age, sex, codon 129 genotype, 14-3-3 in the cerebrospinal fluid (CSF), and CSF tau concentrations. The prognostic accuracy for overall survival was measured by the c statistics of multivariable Cox proportional hazard models. A score chart was derived to predict 6-month survival and median survival time.

Results: A model containing age, sex, codon 129 genotype, and CSF tau (with two-way interactions) was selected as the model with the highest c statistic (0.686, 95% confidence interval: 0.665-0.707) in a cross-validation approach.

Discussion: We developed the first prognostic model for overall survival of sCJD patients based on readily available information only. The developed score chart serves as a hands-on prediction tool for clinical practice.
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http://dx.doi.org/10.1002/alz.12133DOI Listing
October 2020

Increased alpha-synuclein tear fluid levels in patients with Parkinson's disease.

Sci Rep 2020 05 22;10(1):8507. Epub 2020 May 22.

Department of Neurology, University Medical Center, Göttingen, Germany.

The objective of the study was to estimate if altered levels of alpha-synuclein can be detected in tear fluid of patients with Parkinson's disease (PD). Therefore, tear fluid samples of 75 PD patients, 75 control subjects and 31 atypical Parkinsonian patients were collected and analyzed in triplicates using an ultra-sensitive single molecule array (SIMOA) system and applying a human alpha-synuclein immunoassay. In PD, levels of total soluble alpha-synuclein were significantly increased compared to control subjects (p = 0.03; AUC PD vs. controls 0.60). There was no difference comparing PD patients stratified by Hoehn & Yahr stages and atypical Parkinsonian syndromes stratified by tauopathies and non-PD-synucleinopathies against each other (p > 0.05). In conclusion, alpha-synuclein can be detected and quantified in tear fluid, revealing small but significant differences in total alpha-synuclein levels between PD and control subjects. Tear fluid can be collected non-invasively and risk-free, therefore presenting a promising source for further biomarker research.
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http://dx.doi.org/10.1038/s41598-020-65503-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244583PMC
May 2020

A new tetra-plex fluorimetric assay for the quantification of cerebrospinal fluid β-amyloid42, total-tau, phospho-tau and α-synuclein in the differential diagnosis of neurodegenerative dementia.

J Neurol 2020 Sep 5;267(9):2567-2581. Epub 2020 May 5.

Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Barcelona, Spain.

Background: Differential diagnosis of neurodegenerative dementia is currently supported by biomarkers including cerebrospinal fluid (CSF) tests. Among them, CSF total-tau (t-tau), phosphorylated tau (p-tau) and β-amyloid42 (Aβ42) are considered core biomarkers of neurodegeneration. In the present work, we hypothesize that simultaneous assessment of these biomarkers together with CSF α-synuclein (α-syn) will significantly improve the differential diagnostic of Alzheimer's disease and other dementias. To that aim, we characterized the analytical and clinical performance of a new tetra-plex immunoassay that simultaneously quantifies CSF Aβ42, t-tau, p-tau and α-syn in the differential diagnosis of neurodegenerative dementia.

Methods: Biomarkers' concentrations were measured in neurological controls (n = 38), Alzheimer's disease (n = 35), Creutzfeldt-Jakob disease (n = 37), vascular dementia (n = 28), dementia with Lewy bodies/Parkinson's disease dementia (n = 27) and frontotemporal dementia (n = 34) using the new tetra-plex assay and established single-plex assays. Biomarker's performance was evaluated and diagnostic accuracy in the discrimination of diagnostic groups was determined using partial least squares discriminant analysis.

Results: The tetra-plex assay presented accuracies similar to individual single-plex assays with acceptable analytical performance. Significant correlations were observed between tetra-plex and single-plex assays. Using partial least squares discriminant analysis, Alzheimer's disease and Creutzfeldt-Jakob disease were well differentiated, reaching high accuracies in the discrimination from the rest of diagnostic groups.

Conclusions: The new tetra-plex assay coupled with multivariate analytical approaches becomes a valuable asset for the differential diagnosis of neurodegenerative dementia and related applications.
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http://dx.doi.org/10.1007/s00415-020-09870-9DOI Listing
September 2020

The role of cellular prion protein in lipid metabolism in the liver.

Prion 2020 12;14(1):95-108

Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

Cellular prion protein (PrPC) is a plasma membrane glycophosphatidylinositol-anchored protein and it is involved in multiple functions, including neuroprotection and oxidative stress. So far, most of the PrPC functional research is done in neuronal tissue or cell lines; the role of PrPC in non-neuronal tissues such as liver is only poorly understood. To characterize the role of PrPC in the liver, a proteomics approach was applied in the liver tissue of PrPC knockout mice. The proteome analysis and biochemical validations showed an excessive fat accumulation in the liver of PrPC knockout mice with a change in mRNA expression of genes linked to lipid metabolism. In addition, the higher Bax to Bcl2 ratio, up-regulation of tgfb1 mRNA expression in PrPC knockout mice liver, further showed the evidences of metabolic disease. Over-expression of PrPC in fatty acid-treated AML12 hepatic cell line caused a reduction in excessive intracellular fat accumulation; shows association of PrPC levels and lipid metabolism. Therefore, based on observation of excessive fat globules in the liver of ageing PrPC knockout mice and the reduction of fat accumulation in AML12 cell line with PrPC over-expression, the role of PrPC in lipid metabolism is described.
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http://dx.doi.org/10.1080/19336896.2020.1729074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153832PMC
December 2020

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease.

Biomolecules 2020 02 12;10(2). Epub 2020 Feb 12.

Department of Neurology, National Reference Center for CJD Surveillance, University Medical Centre Göttingen, 37075 Göttingen, Germany.

Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt-Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.
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http://dx.doi.org/10.3390/biom10020290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072321PMC
February 2020

Cerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia.

Nat Commun 2020 01 30;11(1):619. Epub 2020 Jan 30.

Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.

The clinical diagnosis of vascular dementia (VaD) is based on imaging criteria, and specific biochemical markers are not available. Here, we investigated the potential of cerebrospinal fluid (CSF) lipocalin 2 (LCN2), a secreted glycoprotein that has been suggested as mediating neuronal damage in vascular brain injuries. The study included four independent cohorts with a total n = 472 samples. LCN2 was significantly elevated in VaD compared to controls, Alzheimer's disease (AD), other neurodegenerative dementias, and cognitively unimpaired patients with cerebrovascular disease. LCN2 discriminated VaD from AD without coexisting VaD with high accuracy. The main findings were consistent over all cohorts. Neuropathology disclosed a high percentage of macrophages linked to subacute infarcts, reactive astrocytes, and damaged blood vessels in multi-infarct dementia when compared to AD. We conclude that CSF LCN2 is a promising candidate biochemical marker in the differential diagnosis of VaD and neurodegenerative dementias.
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http://dx.doi.org/10.1038/s41467-020-14373-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992814PMC
January 2020

Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays.

Transl Neurodegener 2020 17;9. Epub 2020 Jan 17.

1Department of Neurology, University Medicine Goettingen and the German Center for Neurodegenerative Diseases (DZNE), Robert-Koch -Straße 40, 37075 Göttingen, Germany.

Background: α-Synuclein is a small soluble protein, whose physiological function in the healthy brain is poorly understood. Intracellular inclusions of α-synuclein, referred to as Lewy bodies (LBs), are pathological hallmarks of α-synucleinopathies, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB).

Main Body: Understanding of the molecular basis as well as the factors or conditions promoting α-synuclein misfolding and aggregation is an important step towards the comprehension of pathological mechanism of α-synucleinopathies and for the development of efficient therapeutic strategies. Based on the conversion and aggregation mechanism of α-synuclein, novel diagnostic tests, such as protein misfolding seeded conversion assays, e.g. the real-time quaking-induced conversion (RT-QuIC), had been developed. In diagnostics, α-synuclein RT-QuIC exhibits a specificity between 82 and 100% while the sensitivity varies between 70 and 100% among different laboratories. In addition, the α-synuclein RT-QuIC can be used to study the α-synuclein-seeding-characteristics of different α-synucleinopathies and to differentiate between DLB and PD.

Conclusion: The variable diagnostic accuracy of current α-synuclein RT-QuIC occurs due to different protocols, cohorts and material etc.. An impact of micro-environmental factors on the α-synuclein aggregation and conversion process and the occurrence and detection of differential misfolded α-synuclein types or strains might underpin the clinical heterogeneity of α-synucleinopathies
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http://dx.doi.org/10.1186/s40035-019-0181-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966864PMC
January 2020

Chromogranin A Analysis in the Differential Diagnosis Across Lewy Body Disorders.

J Alzheimers Dis 2020 ;73(4):1355-1361

Department of Neurology, Clinical Dementia Centre and DZNE, University Medical School, Georg-August University, Göttingen, Germany.

Background: Chromogranin A (CgA) is a general marker of gut endocrine cells, which are part of the "gut-brain axis" in Parkinson's disease (PD).

Objective: We analyzed CgA as a marker of synaptic dysfunction to assess its role in the differential diagnosis across different Lewy body disorders.

Methods: We analyzed the CgA levels in the cerebrospinal fluid (CSF) and serum from 54 patients covering the spectrum of Lewy body disorders [13 Parkinson's disease (PD), 17 Parkinson's disease dementia (PDD), 24 dementia with Lewy bodies (DLB)] and 14 controls using an ELISA.

Results: A positive correlation was noted between CSF and serum CgA levels (ρ= 0.47, 95% CI: 0.24 to 0.65, p < 0.0001). The highest values of CgA in CSF and in serum were measured in DLB and there was a significant difference between DLB and PDD (p = 0.03 and p = 0.004). The serum levels of CgA in controls achieved lower values compared to DLB (p = 0.006). There was a gradual increase in serum levels from PD to PDD and DLB. An inverse correlation was seen between the CSF level of CgA and Aβ42 (ρ  = -0.296, 95% CI: -0.51 to -0.04, p = 0.02).

Conclusion: The incorporation of CgA analysis as an additional biomarker may be useful in the diagnostic work-up of Lewy body dementia. CgA analysis may be relevant in distinguishing DLB from PDD patients and presumably early stages of PD. Our data on altered serum levels in DLB pave the way to the development of blood-based parameters for the differential diagnosis, which however needs to be confirmed in a prospective study.
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http://dx.doi.org/10.3233/JAD-191153DOI Listing
January 2020

Validation of Poly(Propylene Imine) Glycodendrimers Towards Their Anti-prion Conversion Efficiency.

Mol Neurobiol 2020 Apr 17;57(4):1863-1874. Epub 2019 Dec 17.

Department of Neurology, University Medicine Goettingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

Prion diseases, such as the sporadic Creutzfeldt-Jakob disease (sCJD), are a class of fatal neurodegenerative disorders. Currently, there is no efficient treatment or therapy available. Hence, the search for molecules that may inhibit the conversion of the cellular prion protein (PrP) into its pathological counterpart PrPScrapie (PrP) is of great urgency. Here, we report the generation- and dose-dependent biological action of dense-shell poly(propylene imine) (PPI) glycodendrimers by using scrapie-infected neuroblastoma (ScN2a) cells and the real-time quaking-induced conversion assay (RT-QuIC) for validation of anti-prion efficiencies. Whereas the 2nd and 3rd generation of PPI glycodendrimers exhibited anti-prion conversion efficiency in ScN2a cells validated by RT-QuIC analysis, we observed that the 4th generation of glycodendrimers had shown no significant effect. Translational RT-QuIC studies conducted with human prions derived from sCJD patients indicated an anti-prion conversion effect (not on PrP degradation) of PPI glycodendrimers against human prions with the highest inhibitory activity of the 4th generation of PPI glycodendrimers towards prion aggregation compared to the 2nd and 3rd generation. In conclusion, our study highlights the potential of PPI glycodendrimers as therapeutic compounds due to their anti-conversion activity on human prions in a PrP strain depending manner.
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http://dx.doi.org/10.1007/s12035-019-01837-wDOI Listing
April 2020

Evaluation of Human Cerebrospinal Fluid Malate Dehydrogenase 1 as a Marker in Genetic Prion Disease Patients.

Biomolecules 2019 11 28;9(12). Epub 2019 Nov 28.

Department of Neurology, National Reference Center for CJD Surveillance University Medical Center Göttingen, 37075 Göttingen, Germany.

The exploration of accurate diagnostic markers for differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous study on cerebrospinal fluid (CSF)-mitochondrial malate dehydrogenase 1 (MDH1) in sporadic Creutzfeldt-Jakob disease (sCJD) patients revealed a highly significant upregulation of MDH1. Here, we measured the CSF levels of MDH1 via enzyme-linked immunosorbent assay in a cohort of rare genetic prion disease cases, such as genetic CJD (gCJD) cases, exhibiting the E200K, V210I, P102L (Gerstmann-Sträussler-Scheinker syndrome (GSS)), or D178N (fatal familial insomnia (FFI)) mutations in the . Interestingly, we observed enhanced levels of CSF-MDH1 in all genetic prion disease patients compared to neurological controls (without neurodegeneration). While E200K and V210I carriers showed highest levels of MDH1 with diagnostic discrimination from controls of 0.87 and 0.85 area under the curve (AUC), FFI and GSS patients exhibited only moderately higher CSF-MDH1 levels than controls. An impact of the codon 129 methionine/valine (MV) genotype on the amount of MDH1 could be excluded. A correlation study of MDH1 levels with other neurodegenerative marker proteins revealed a significant positive correlation between CSF-MDH1 concentration with total tau (tau) but not with 14-3-3 in E200K, as well as in V210I patients. In conclusion, our study indicated the potential use of MDH1 as marker for gCJD patients which may complement the current panel of diagnostic biomarkers.
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http://dx.doi.org/10.3390/biom9120800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995564PMC
November 2019

The novel seizure quality index for the antidepressant outcome prediction in electroconvulsive therapy: association with biomarkers in the cerebrospinal fluid.

Eur Arch Psychiatry Clin Neurosci 2020 Oct 23;270(7):911-919. Epub 2019 Nov 23.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

For patients with depression treated with electroconvulsive therapy (ECT), the novel seizure quality index (SQI) can predict the risk of non-response (and non-remission)-as early as after the second ECT session-based the extent of several ictal parameters of the seizure. We aim to test several CSF markers on their ability to predict the degree of seizure quality, measured by the SQI to identify possible factors, that could explain some variability of the seizure quality. Baseline CSF levels of metabolites from the kynurenine pathway, markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system, endocannabinoids, sphingolipids, neurotrophic factors (VEGF) and Klotho were measured before ECT in patients with depression (n = 12) to identify possible correlations with the SQI by Pearson's partial correlation. Negative, linear relationships with the SQI for response were observed for CSF levels of T-tau (r = - 0.69, p = 0.019), phosphatidylcholines (r = - 0.52, p = 0.038) and IL-8 (r = - 0.67, p = 0.047). Regarding the SQI for remission, a negative, linear relationship was noted with CSF levels of the endocannabinoid AEA (r = - 0.70, p = 0.024) and CD163 (r = - 0.68, p = 0.029). In sum, CSF Markers for the innate immune system, for neurodegeneration and from lipids were found to be associated with the SQI for response and remission after adjusting for age. Consistently, higher CSF levels of the markers were always associated with lower seizure quality. Based on these results, further research regarding the mechanism of seizure quality in ECT is suggested.
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http://dx.doi.org/10.1007/s00406-019-01086-xDOI Listing
October 2020

Cerebrospinal fluid non-phosphorylated tau in the differential diagnosis of Creutzfeldt-Jakob disease: a comparative prospective study with 14-3-3.

J Neurol 2020 Feb 7;267(2):543-550. Epub 2019 Nov 7.

Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.

Cerebrospinal fluid (CSF) non-phosphorylated tau (non-p-tau) is increased in sporadic Creutzfeldt-Jakob disease (CJD), but its accuracy in the differential diagnosis has not been previously established. Here, we first used a retrospective cohort of non-CJD (n = 135) and CJD (n = 137) cases to determine the optimal cutoff point for the discrimination of CJD cases. Next, we prospectively quantified non-p-tau and 14-3-3 protein in a cohort of 1427 cases received for CSF testing at the German National Reference Center for transmissible spongiform encephalopathies. Among them, 36 were subsequently diagnosed as CJD. The diagnostic accuracy of both proteins discriminating CJD cases was evaluated. Using a cutoff of 650 pg/mL, non-p-tau displayed 94.39% accuracy in discriminating CJD cases, while 92.92% accuracy was achieved by 14-3-3 using a cutoff of 20,000 AU/mL. Diagnostic test evaluation for both proteins showed a slightly better performance of non-p-tau compared to 14-3-3. The two biomarkers' concentrations showed a significant positive correlation, both in the total population and in CJD cases (p < 0.001). Finally, the analysis of CSF non-p-tau concentrations when undergoing pre-analytical factors showed high stability in front of temperature storage and freeze/thaw cycles. Therefore, we conclude that when used in the appropriate clinical context of a prion disease surveillance center, non-p-tau is a highly sensitive and specific diagnostic marker for CJD.
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http://dx.doi.org/10.1007/s00415-019-09610-8DOI Listing
February 2020

The cellular prion protein and its derived fragments in human prion diseases and their role as potential biomarkers.

Expert Rev Mol Diagn 2019 11 26;19(11):1007-1018. Epub 2019 Sep 26.

Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen , Göttingen , Germany.

: Human prion diseases are a heterogeneous group of incurable and debilitating conditions characterized by a progressive degeneration of the central nervous system. The conformational changes of the cellular prion protein and its formation into an abnormal isoform, spongiform degeneration, neuronal loss, and neuroinflammation are central to prion disease pathogenesis. It has been postulated that truncated variants of aggregation-prone proteins are implicated in neurodegenerative mechanisms. An increasing body of evidence indicates that proteolytic fragments and truncated variants of the prion protein are formed and accumulated in the brain of prion disease patients. These prion protein variants provide a high degree of relevance to disease pathology and diagnosis. : In the present review, we summarize the current knowledge on the occurrence of truncated prion protein species and their potential roles in pathophysiological states during prion diseases progression. In addition, we discuss their usability as a diagnostic biomarker in prion diseases. : Either as a primary factor in the formation of prion diseases or as a consequence from neuropathological affection, abnormal prion protein variants and fragments may provide independent information about mechanisms of prion conversion, pathological states, or disease progression.
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http://dx.doi.org/10.1080/14737159.2019.1667231DOI Listing
November 2019

RNA editing alterations define manifestation of prion diseases.

Proc Natl Acad Sci U S A 2019 09 6;116(39):19727-19735. Epub 2019 Sep 6.

Neurodegenerative Diseases Research Group, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece;

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt-Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
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http://dx.doi.org/10.1073/pnas.1803521116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765247PMC
September 2019

Plasma YKL-40 in the spectrum of neurodegenerative dementia.

J Neuroinflammation 2019 Jul 12;16(1):145. Epub 2019 Jul 12.

Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Robert Koch 40, 37075, Göttingen, Germany.

Background: Increased plasma YKL-40 has been reported in Alzheimer's disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias.

Methods: YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed.

Results: Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC (p < 0.001), ND, AD and VaD (p < 0.01) and in LBD compared to HC (p < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages.

Conclusions: Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.
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http://dx.doi.org/10.1186/s12974-019-1531-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624942PMC
July 2019

Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies.

Cell Rep 2019 07;28(1):65-77.e6

Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany; Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Max Planck Institute of Experimental Medicine, Hermann Rein Street 3, Göttingen 37075, Germany. Electronic address:

Alpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice. The levels of superoxide dismutase 2, a client of the HSP10/HSP60 folding complex, and synaptosomal spare respiratory capacity are also reduced. Overexpression of HSP10 ameliorates aSyn-associated mitochondrial dysfunction and delays aSyn pathology in vitro and in vivo. Altogether, our data indicate that increased levels of aSyn induce mitochondrial deficits, at least partially, by sequestering HSP10 in the cytosol and preventing it from acting in mitochondria. Importantly, these alterations manifest first at presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies but opens new avenues for targeting underlying cellular pathologies.
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http://dx.doi.org/10.1016/j.celrep.2019.06.009DOI Listing
July 2019

CSF neurogranin as a neuronal damage marker in CJD: a comparative study with AD.

J Neurol Neurosurg Psychiatry 2019 08 16;90(8):846-853. Epub 2019 May 16.

Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Ministry of Health, L'Hospilatet del Llobregat, Barcelona, Spain

Objective: To investigate whether cerebrospinal fluid (CSF) neurogranin concentrations are altered in sporadic Creutzfeldt-Jakob disease (CJD), comparatively with Alzheimer's disease (AD), and associated with neuronal degeneration in brain tissue.

Methods: CSF neurogranin, total tau, neurofilament light (NFL) and 14-3-3 protein were measured in neurological controls (NCs, n=64), AD (n=46) and CJD (n=81). The accuracy of neurogranin discriminating the three diagnostic groups was evaluated. Correlations between neurogranin and neurodegeneration biomarkers, demographic, genetic and clinical data were assessed. Additionally, neurogranin expression in postmortem brain tissue was studied.

Results: Compared with NC, CSF neurogranin concentrations were increased in CJD (4.75 times of NC; p<0.001, area under curve (AUC), 0.96 (95% CI 0.93 to 0.99) and AD (1.94 times of NC; p<0.01, AUC 0.73, 95% CI 0.62 to 0.82), and were able to differentiate CJD from AD (p<0.001, AUC 0.85, 95% CI 0.78 to 0.92). CSF tau was increased in CJD (41 times of NC) and in AD (3.1 times of NC), both at p<0.001. In CJD, neurogranin positively correlated with tau (r=0.55, p<0.001) and was higher in 14-3-3-positivity (p<0.05), but showed no association with NFL (r=0.08, p=0.46). CJD-MM1/MV1 cases displayed higher neurogranin levels than VV2 cases. Neurogranin was increased at early CJD disease stages and was a good prognostic marker of survival time in CJD. In brain tissue, neurogranin was detected in the cytoplasm, membrane and postsynaptic density fractions of neurons, with reduced levels in AD, and more significantly in CJD, where they correlated with synaptic and axonal markers.

Conclusions: Neurogranin is a new biomarker of prion pathogenesis with diagnostic and prognostic abilities, which reflects the degree of neuronal damage in brain tissue in a CJD subtype manner.
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http://dx.doi.org/10.1136/jnnp-2018-320155DOI Listing
August 2019

Seeding variability of different alpha synuclein strains in synucleinopathies.

Ann Neurol 2019 05 27;85(5):691-703. Epub 2019 Mar 27.

Department of Neurology, University Medicine Goettingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

Objectives: Currently, the exact reasons why different α-synucleinopathies exhibit variable pathologies and phenotypes are still unknown. A potential explanation may be the existence of distinctive α-synuclein conformers or strains. Here, we intend to analyze the seeding activity of dementia with Lewy bodies (DLB) and Parkinson's disease (PD) brain-derived α-synuclein seeds by real-time quaking-induced conversion (RT-QuIC) and to investigate the structure and morphology of the α-synuclein aggregates generated by RT-QuIC.

Methods: A misfolded α-synuclein-enriched brain fraction from frontal cortex and substantia nigra pars compacta tissue, isolated by several filtration and centrifugation steps, was subjected to α-synuclein/RT-QuIC analysis. Our study included neuropathologically well-characterized cases with DLB, PD, and controls (Ctrl). Biochemical and morphological analyses of RT-QuIC products were conducted by western blot, dot blot analysis, Raman spectroscopy, atomic force microscopy, and transmission electron microscopy.

Results: Independently from the brain region, we observed different seeding kinetics of α-synuclein in the RT-QuIC in patients with DLB compared to PD and Ctrl. Biochemical characterization of the RT-QuIC product indicated the generation of a proteinase K-resistant and fibrillary α-synuclein species in DLB-seeded reactions, whereas PD and control seeds failed in the conversion of wild-type α-synuclein substrate.

Interpretation: Structural variances of α-synuclein seeding kinetics and products in DLB and PD indicated, for the first time, the existence of different α-synuclein strains in these groups. Therefore, our study contributes to a better understanding of the clinical heterogeneity among α-synucleinopathies, offers an opportunity for a specific diagnosis, and opens new avenues for the future development of strain-specific therapies. Ann Neurol 2019;85:691-703.
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http://dx.doi.org/10.1002/ana.25446DOI Listing
May 2019

Cerebrospinal fluid neurofilament light in suspected sporadic Creutzfeldt-Jakob disease.

J Clin Neurosci 2019 Feb 9;60:124-127. Epub 2018 Oct 9.

Department of Neurology, University Medical School, Göttingen, Germany; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Ministry of Health, L'Hospitalet de Llobregat, Spain; Bellvitge Biomedical Research Institute (IDBELL), L'Hospitalet de Llobregat, Spain. Electronic address:

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease. It is invariably fatal and displays a short clinical disease stage. The key event in sCJD is the propagation of a beta-sheet rich conformer of the physiological PrP protein, known as PrP. Neuropathological disease characteristics include gliosis, neuronal loss and spongiform degeneration; disease clinical manifestations refer to mental and visual disabilities, cognitive impairment, gait or limb ataxia, myoclonus and mutism. Definite sCJD diagnosis requires post-mortem brain material histopathological examination. However, highly certain pre-mortem differential diagnosis is desired to exclude other treatable disorders and to reduce disease transmission risks. Detection and/or quantification of cerebrospinal fluid (CSF) biomarkers reflecting neuronal damage and PrP misfolding in the diseased brain significantly enhance pre-mortem diagnosis. Previously established and newly identified biomarkers are used towards this direction. Increased CSF Neurofilament light chain (NFL) concentrations have been reported in several neurological disorders, including prion diseases. In the present study, we analyzed CSF NFL levels in two independent patient cohorts, consisting of highly suspected sCJD cases that were further classified as sCJD or non-CJD according to established diagnostic criteria. CSF NFL concentrations were increased in sCJD compared to non-CJD cases in both cohorts (area under the curve (with 95% confidence interval) equal to 0.89 (0.82 to 0.97) and 0.86 (0.77 to 0.96), respectively. CSF NFL was associated neither to age nor to sex but correlated with total-tau concentrations in both cohorts. Overall, our data provide independent validation of CSF NFL utility in sCJD differential diagnosis.
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http://dx.doi.org/10.1016/j.jocn.2018.09.031DOI Listing
February 2019

Interlaboratory validation of cerebrospinal fluid α-synuclein quantification in the diagnosis of sporadic Creutzfeldt-Jakob disease.

Alzheimers Dement (Amst) 2018 7;10:461-470. Epub 2018 Jul 7.

Department of Neurology, University Medicine Göttingen, Göttingen, Germany.

Introduction: Cerebrospinal fluid α-synuclein level is increased in sporadic Creutzfeldt-Jakob disease cases. However, the clinical value of this biomarker remains to be established. In this study, we have addressed the clinical validation parameters and the interlaboratory reproducibility by using an electrochemiluminescent assay.

Methods: Cerebrospinal fluid α-synuclein was quantified in a total of 188 sporadic Creutzfeldt-Jakob disease and non-Creutzfeldt-Jakob-disease cases to determine sensitivity and specificity values and lot-to-lot variability. Two round robin tests with 70 additional cases were performed in six independent laboratories.

Results: A sensitivity of 93% and a specificity of 96% were achieved in discriminating sporadic Creutzfeldt-Jakob disease. No differences were detected between lots. The mean interlaboratory coefficient of variation was 23%, and the intralaboratory coefficient of variations ranged 2.70%-11.39%. Overall, 97% of samples were correctly diagnosed.

Discussion: The herein validated α-synuclein assay is robust, accurate, and reproducible in identifying Creutzfeldt-Jakob disease cases. Thus, it is ready for implementation in the clinical practice to support the diagnosis of Creutzfeldt-Jakob disease.
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http://dx.doi.org/10.1016/j.dadm.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171371PMC
July 2018

Cerebrospinal Fluid Total and Phosphorylated α-Synuclein in Patients with Creutzfeldt-Jakob Disease and Synucleinopathy.

Mol Neurobiol 2019 May 22;56(5):3476-3483. Epub 2018 Aug 22.

Department of Neurology, University Medical Center Goettingen, Goettingen, Germany.

High levels of total α-synuclein (t-α-synuclein) in the cerebrospinal fluid (CSF) were reported in sporadic Creutzfeldt-Jakob disease (sCJD). The potential use of t-α-synuclein in the discrimination of Lewy body dementias (i.e., Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB)) is still under investigation. In addition, phospho-serine-129 α-synuclein (p-α-synuclein) has been described to be slightly increased in the CSF of synucleinopathies. Here, we analyzed t-α-synuclein and p-α-synuclein concentrations and their ratio in the context of differential diagnosis of neurodegenerative diseases. We quantified the levels of CSF t-α-synuclein and p-α-synuclein in a cohort of samples composed of neurological controls (NC), sCJD, PDD, and DLB by means of newly developed specific enzyme-linked immunosorbent assays. T-α-synuclein and p-α-synuclein were specifically elevated in sCJD compared to other disease groups. The area under the curve (AUC) values for t-α-synuclein were higher for the discrimination of sCJD from dementias associated to Lewy bodies as compared to the use of p-α-synuclein. A combination of both markers even increased the diagnostic accuracy. An inverse correlation was observed in CSF between t-α-synuclein and p-α-synuclein, especially in the DLB group, indicating a disease-relevant association between both markers. In conclusion, our data confirm t-α-synuclein and p-α-synuclein as robust biomarkers for sCJD and indicate the potential use of colorimetric t-α-synuclein ELISAs for differential diagnosis of dementia types.
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http://dx.doi.org/10.1007/s12035-018-1313-4DOI Listing
May 2019

Biomarkers for Antidepressant Efficacy of Electroconvulsive Therapy: An Exploratory Cerebrospinal Fluid Study.

Neuropsychobiology 2019 17;77(1):13-22. Epub 2018 Aug 17.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

Background: No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet.

Method: Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system (interleukin [IL]-6, neopterin, soluble CD14, soluble CD163, migration inhibitory factor and monocyte chemotactic protein 1), endocannabinoids, sphingolipids and Klotho before ECT in patients with depression (n = 12) to identify possible correlations with the clinical antidepressant response to ECT.

Results: Correlation with the reduction of the depressive symptoms could be observed especially for markers of neurodegeneration and elements of the innate immune system. Differences for CSF levels of several markers were found between the groups of responders and non-responders at the trend level.

Limitations: The sample size is small and the -distribution of responders and non-responders is uneven.

Conclusions: It is this first study on CSF biomarkers for antidepressant efficacy of ECT warrants further research regarding the mechanism of ECT and personalized antidepressant therapy.
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http://dx.doi.org/10.1159/000491401DOI Listing
December 2018

Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases.

Mol Neurobiol 2019 Apr 30;56(4):2811-2821. Epub 2018 Jul 30.

Department of Neurology, University Medical School, Göttingen, Germany.

Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.
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http://dx.doi.org/10.1007/s12035-018-1251-1DOI Listing
April 2019

CSF nonphosphorylated Tau as a biomarker for the discrimination of AD from CJD.

Ann Clin Transl Neurol 2018 Jul 26;5(7):883-887. Epub 2018 May 26.

Clinical Dementia Center Department of Neurology University Medical School Göttingen Germany.

Creutzfeldt-Jakob disease and Alzheimer's disease are characterized by the presence of elevated total-Tau cerebrospinal fluid concentrations while the presence of hyperphosphorylated Tau forms in the cerebrospinal fluid is rather a hallmark of Alzheimer's disease. Here we aimed to investigate potential contribution of nonphospho-Tau epitopes (non-P-Tau) in the discrimination between both diseases. Non-P-Tau cerebrospinal fluid concentration was highly increased in Creutzfeldt-Jakob disease ( = 57, 3683 ± 3599 pg/mL) compared to Alzheimer's disease ( = 41, 148 ± 219 pg/mL) and neurological controls ( = 56, 62 ± 40 pg/mL), and significantly improved the proportion of correctly classified patients (99%) compared to that achieved by total-Tau (90%), P-Tau (62%) and 14-3-3 (91%).
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http://dx.doi.org/10.1002/acn3.584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043772PMC
July 2018

Validation and utilization of amended diagnostic criteria in Creutzfeldt-Jakob disease surveillance.

Neurology 2018 07 22;91(4):e331-e338. Epub 2018 Jun 22.

From the National TSE Reference Center (P.H., M.L., T.K., S.G., J.T., M.C., M.S., I.Z.), Department of Neurology, Georg-August University Goettingen; Institute of Neuropathology (M.G., J.M.), University Medical Center Hamburg-Eppendorf, Hamburg; and Institute of Neuropathology (W.S.-S.), Saarland University Medical Center, Germany.

Objective: To validate an amended protocol for clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) including real-time quaking-induced conversion (RT-QuIC) and to observe its use in CJD surveillance.

Methods: In the framework of a prospective epidemiologic study, all neuropathologically confirmed cases with sCJD who received CSF RT-QuIC analysis during diagnostic workup (n = 65) and a control group of individuals without CJD (n = 118) were selected to investigate the accuracy of an amended diagnostic protocol. The patients had been referred to the German National Reference Center for Transmissible Spongiform Encephalopathies. The influence of the amended protocol on incidence figures was evaluated in the context of 3 years of surveillance activity (screened cases using 14-3-3 test n = 18,789, highly suspicious cases of CJD n = 704). Annual incidences were calculated with current criteria and the amended protocol.

Results: The amended protocol showed a sensitivity of 97% and a specificity of 99%. When it was applied to all suspected cases who were referred to the reference center, the assessed incidence of CJD increased from 1.7 to 2.2 per million in 2016.

Conclusion: CJD surveillance remains challenging because information from external health care institutions can be limited. RT-QuIC shows excellent diagnostic accuracy when applied in the clinical setting to symptomatic patients. Data for RT-QuIC alone when applied as a general screening test are not available yet. We propose an amended research protocol that improves early and accurate clinical diagnosis of sCJD during surveillance activities. The use of this protocol will probably lead to a significant increase of the incidence rate.

Classification Of Evidence: This study provides Class III evidence that for patients with suspected sCJD, criteria for clinical diagnosis plus the CSF RT-QuIC accurately identifies patients with sCJD (sensitivity 97%, specificity 99%).
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http://dx.doi.org/10.1212/WNL.0000000000005860DOI Listing
July 2018

Amplification and Detection of Minuscule Amounts of Misfolded Prion Protein by Using the Real-Time Quaking-Induced Conversion.

Methods Mol Biol 2018 ;1779:257-263

Department of Neurology, University Medicine Goettingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen, Göttingen, Germany.

A characteristic feature of transmissible spongiform encephalopathies (TSE) is the progressive accumulation of protein aggregates in the brain in a self-propagation manner. Based on this mechanism, in vitro protein amplification systems (such as real-time quaking-induced conversion (RT-QuIC)) for the detection of misfolded prion protein scrapie (PrP) in CSF were a major step in pre-mortem diagnosis of human prion diseases. Here, we describe a protocol of the RT-QuIC assay to detect PrP in CSF of prion disease patients. This methodology depends on prion seeds that induce misfolding and aggregation of a substrate by cycles of incubation and quaking. Besides diagnostics, further applications of the RT-QuIC appear to be promising for discrimination between different PrP subtypes or strains, understanding the mechanism of protein misfolding and pre-screening of anti-prion drugs. The technique can be further developed to be used to study characteristics of misfolded proteins in other "prion like" diseases, such as tauopathies, synucleinopathies, or amyloidopathies.
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http://dx.doi.org/10.1007/978-1-4939-7816-8_16DOI Listing
July 2019