Publications by authors named "Daniela Varges"

28 Publications

  • Page 1 of 1

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-09870-9DOI Listing
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-14373-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992814PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-191153DOI Listing
January 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-019-1531-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624942PMC
July 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-018-1313-4DOI Listing
May 2019

Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson's disease dementia.

Eur Arch Psychiatry Clin Neurosci 2020 Jun 6;270(4):461-470. Epub 2018 Aug 6.

Department of Neurology, Clinical Dementia Center and DZNE, National TSE Reference Centre, University Medical School, Georg-August University, Robert-Koch-Str. 40, 37073, Göttingen, Germany.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share a couple of clinical similarities that is often a source of diagnostic pitfalls. We evaluated the discriminatory potential of brain-derived CSF markers [tau, p-tau (181P), Aβ, NSE and S100B] across the spectrum of Lewy body disorders and assessed whether particular markers are associated with cognitive status in investigated patients. The tau CSF level, amyloid β and p-tau/tau ratio were helpful in the distinction between DLB and PDD (p = 0.04, p = 0.002 and p = 0.02, respectively) as well as from PD patients (p < 0.001, p = 0.001 and p = 0.002, respectively). Furthermore, the p-tau/tau ratio enabled the differentiation of DLB with mild dementia from PDD patients (p = 0.02). The CSF tau and p-tau levels in DLB and CSF tau and p-tau/tau ratio in PDD patients reflected the severity of dementia. Rapid disease course was associated with the decrease of Aβ in DLB but not in PDD. Elevation of S100B in DLB (p < 0.0001) as well as in PDD patients (p = 0.002) in comparison to controls was estimated. Hence, with the appropriate clinical context; the CSF marker profile could be helpful in distinguishing DLB from PDD patients even in early stages of dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00406-018-0928-9DOI Listing
June 2020

Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: Evaluation of diagnostic accuracy in the differential diagnosis of prion diseases.

Alzheimers Dement 2018 06 3;14(6):751-763. Epub 2018 Feb 3.

Network Center for Biomedical Research in Neurodegenerative Diseases, (CIBERNED), Institute Carlos III, Ministry of Health, Hospitalet de Llobregat, Barcelona, Spain. Electronic address:

Introduction: Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown.

Methods: Cerebrospinal fluid NFL levels were quantified in nonprimarily neurodegenerative neurological and psychiatric diseases (n = 122), mild cognitive impairment (n = 48), Alzheimer's disease (n = 108), dementia with Lewy bodies/Parkinson's disease dementia (n = 53), vascular dementia (n = 46), frontotemporal dementia (n = 41), sporadic Creutzfeldt-Jakob disease (sCJD, n = 132), and genetic prion diseases (n = 182).

Results: The highest NFL levels were detected in sCJD, followed by vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease dementia, Alzheimer's disease, and mild cognitive impairment. In sCJD, NFL levels correlated with cerebrospinal fluid tau and disease duration. NFL levels were able to differentiate sCJD from nonprimarily neurodegenerative neurological and psychiatric diseases (area under the curve = 0.99, 95% confidence interval: 0.99-1) and from the other diagnostic groups showing cognitive impairment/dementia of a non-CJD etiology (area under the curve = 0.90, 95% confidence interval: 0.87-0.92). Compared to nonprimarily neurodegenerative neurological and psychiatric diseases, NFL was also elevated in genetic prion diseases associated with the E200K, V210I, P102L, and D178N prion protein gene mutations.

Discussion: Increased NFL levels are a common feature in neurodegenerative dementias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2017.12.008DOI Listing
June 2018

Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany.

J Alzheimers Dis 2017 ;59(1):329-337

Department of Neurology, University Medical School, Georg-August University Göttingen, Germany.

Background: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD.

Objective: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype.

Methods: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type.

Results: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes.

Conclusion: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-161129DOI Listing
April 2018

Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases.

Alzheimers Dement 2017 Jun 18;13(6):710-719. Epub 2016 Nov 18.

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

Introduction: Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context.

Methods: We established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111).

Results: An optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD). Genetic CJD cases showed increased CSF α-synuclein values. No increased α-synuclein levels were detected in non-CJD cases with rapid progression course.

Discussion: Detection of α-synuclein in the CSF of patients with suspected CJD is a valuable diagnostic test reaching almost full discrimination from non-prion disease cases. These data highlight the utility of CSF α-synuclein quantification in front of classical CSF biomarkers in clinical routine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2016.09.013DOI Listing
June 2017

Doxycycline in early CJD: a double-blinded randomised phase II and observational study.

J Neurol Neurosurg Psychiatry 2017 Feb 2;88(2):119-125. Epub 2016 Nov 2.

Department of Neurology, National Reference Center for TSE Surveillance, University Medical Center Goettingen, Göttingen, Germany.

Objectives: The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD).

Methods: From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival.

Results: Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)).

Conclusions: On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD.

Trial Registration Number: EudraCT 2006-003934-14; Results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2016-313541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284486PMC
February 2017

Cerebrospinal α-synuclein in α-synuclein aggregation disorders: tau/α-synuclein ratio as potential biomarker for dementia with Lewy bodies.

J Neurol 2016 Nov 20;263(11):2271-2277. Epub 2016 Aug 20.

Department of Neurology, Clinical Dementia Center, University Medical Center, Georg-August University, Robert Koch Strasse 40, Göttingen, Germany.

Several studies have addressed the utility of cerebrospinal (CSF) α-synuclein levels as a potential biomarker of α-synuclein aggregation disorders. However, its relevance in the differential diagnostic context of neurodegenerative and movement disorders is still a contentious subject. Here, we report total CSF α-synuclein levels in a cohort of clinically diagnosed α-synuclein-related disorders encompassing Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies and multiple system atrophy in comparison to essential tremor and neurological control cases. α-synuclein levels in α-synuclein-related disorders were significantly lower than in controls (p < 0.001). However, in the differential diagnostic context, only Parkinson's disease cases presented significant lower α-synuclein levels compared to essential tremor and neurological controls. In cases with clinically diagnosed α-synuclein pathology, CSF α-synuclein levels showed a moderate positive correlation with CSF tau and p-tau, but not with Aβ42 levels. Due to elevated CSF tau levels in dementia with Lewy bodies samples, tau/α-synuclein ratio showed a good clinical accuracy in discriminating controls from dementia with Lewy bodies cases (AUC = 0.8776) compared to single α-synuclein (AUC = 0.7192) and tau (AUC = 0.7739) levels. In conclusion, α-synuclein alone lacks of clinical value as a biomarker of α-synuclein-related disorders, but in combination with total tau, it may improve the diagnosis of dementia with Lewy bodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-016-8259-0DOI Listing
November 2016

Application of an in vitro-amplification assay as a novel pre-screening test for compounds inhibiting the aggregation of prion protein scrapie.

Sci Rep 2016 07 7;6:28711. Epub 2016 Jul 7.

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

In vitro amplification assays, such as real-time quaking-induced conversion (RT-QuIC) are used to detect aggregation activity of misfolded prion protein (PrP) in brain, cerebrospinal fluid (CSF) and urine samples from patients with a prion disease. We believe that the method also has a much broader application spectrum. In the present study, we applied RT-QuIC as a pre-screening test for substances that potentially inhibit the aggregation process of the cellular PrP (PrP(C)) to proteinase (PK)-resistant PrP(res). We chose doxycycline as the test substance as it has been tested successfully in animal models and proposed in clinical studies as a therapeutic for prion diseases. The RT-QuIC-reaction was seeded with brain tissue or CSF from sCJD patients and doxycycline was then added in different concentrations as well as at different time points. In both experiments, we observed a dose- and time-dependent inhibition of the RT-QuIC seeding response and a decrease of PK resistant PrP(res) when doxycycline was added. In contrast, ampicillin or sucrose had no effect on the RT-QuIC seeding response. Our study is the first to apply RT-QuIC as a pre-screening assay for compounds inhibiting the PrP aggregation in vitro and confirms that doxycycline is an efficient inhibitor of the PrP aggregation process in RT-QuIC analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep28711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935936PMC
July 2016

Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia.

Alzheimers Dement 2016 05 21;12(5):577-89. Epub 2015 Dec 21.

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

Introduction: The analysis of cerebrospinal fluid biomarkers gains importance in clinical routine and is effective in substantiating dementia diagnosis in the differential diagnostic context.

Methods: We evaluated the levels of β-amyloid (Aβ) 42, Aβ40, tau, and P-tau in a large patient population subdivided into prion diseases, tauopathies, synucleinopathies, and controls. Diagnostic test evaluation was assessed by ROC area under the curve analysis.

Results: High tau levels were detected in sporadic Creutzfeldt-Jakob disease (sCJD) and high P-tau levels in Alzheimer's disease (AD) and sCJD. Aβ40 was lower exclusively in prionopathies, but low Aβ42 was detected in AD, sCJD, and Lewy body dementia. When disease groups were stratified according to the underlying proteinopathy, we detected disease-type specificities for all biomarkers. P-tau/tau, Aβ42/40, Aβ42/tau, and Aβ40/tau ratios proved valuable in discriminating disease groups and controls, especially P-tau/tau ratio in the identification of sCJD cases.

Discussion: Combining the biomarker panel allows differentiating between various types of neurodegenerative dementias and contributes to a better understanding of their pathophysiological processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2015.10.009DOI Listing
May 2016

Increased albumin CSF/serum ratio in dementia with Lewy bodies.

J Neurol Sci 2015 Nov 23;358(1-2):398-403. Epub 2015 Oct 23.

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

Background: Alterations in the CSF/serum albumin ratio (Qalb) is currently recognized as one of the most reliable markers of blood-brain barrier impairment and blood-CSF barrier permeability, but its potential role as a biomarker in the differential diagnosis of neurological diseases has been poorly analysed.

Methods: We evaluated Qalb and core CSF biomarkers (Tau, p-Tau and Aβ42) in a large patient population of neurological and neurodegenerative cases. Diagnostic test evaluation was assessed by ROC-AUC analysis.

Results: In the differential diagnostic analysis, increased Qalb was found in dementia with Lewy bodies (DLB) patients compared to other diseases, either individually or stratified in non-dementia and dementia groups. When clinical groups were analysed individually and compared to controls, Qalb was also increased in stroke and Parkinson's disease dementia (PDD) cases, but not in Parkinson's disease (PD). Qalb in DLB cases correlate with CSF Aβ42 levels but not with Tau and p-Tau levels. Due to the lower CSF Aβ42 levels in DLB compared to PD and PDD, the potential clinical applicability of Qalb with respect to the DLB diagnosis is increased in combination with CSF Aβ42 analysis.

Conclusions: The present study demonstrates increased Qalb in synucleinopathies associated with dementia revealing a potential new clinical approach for the differential diagnosis of DLB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2015.10.011DOI Listing
November 2015

Clinical findings and diagnosis in genetic prion diseases in Germany.

Eur J Epidemiol 2016 Feb 16;31(2):187-96. Epub 2015 Jun 16.

Department of Neurology, National Reference Center for TSE Surveillance, University Medical School, Georg-August University Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.

To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-015-0049-yDOI Listing
February 2016

Stability and Reproducibility Underscore Utility of RT-QuIC for Diagnosis of Creutzfeldt-Jakob Disease.

Mol Neurobiol 2016 Apr 1;53(3):1896-1904. Epub 2015 Apr 1.

Department of Neurology, University Medical Center Goettingen and German Center for Neurodegenerative Diseases (DZNE)-site Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.

Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP(Sc)). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, "blinded" ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluorescence units (rfu), we obtained a sensitivity of 85% and a specificity of 99%. The multi-centre inter-laboratory reproducibility of RT-QuIC revealed a Fleiss' kappa value of 0.83 (95% CI: 0.40-1.00) indicating an almost perfect agreement. Moreover, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP(Sc) seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/μL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days) can be rescued by removal of erythrocytes. The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT-QuIC as an innovative and robust diagnostic method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-015-9133-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789202PMC
April 2016

Characteristic CSF prion seeding efficiency in humans with prion diseases.

Mol Neurobiol 2015 Feb 9;51(1):396-405. Epub 2014 May 9.

Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrP(Sc)) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrP(Sc) type, and other disease-related factors on the real-time quaking-induced conversion (RT-QuIC) response. We analyzed times to 10,000 relative fluorescence units, areas under the curve and the signal maximum of RT-QuIC response as seeding parameters of interest. Interestingly, type of prion disease (sporadic vs. genetic) and the PRNP mutation (E200K vs. V210I and FFI), codon 129 genotype, and PrP(Sc) type affected RT-QuIC response. In genetic forms, type of mutation showed the strongest effect on the observed outcome variables. In sporadic CJD, MM1 patients displayed a higher RT-QuIC signal maximum compared to MV1 and VV1. Age and gender were not associated with RT-QuIC signal, but patients with a short disease course showed a higher seeding efficiency of the RT-QuIC response. This study demonstrated that PrP(Sc) characteristics in the CSF of human prion disease patients are associated with disease subtypes and rate of decline as defined by disease duration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-014-8709-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309904PMC
February 2015

Spongiform encephalopathy in siblings with no evidence of protease-resistant prion protein or a mutation in the prion protein gene.

J Neurol 2013 Jul 2;260(7):1871-9. Epub 2013 Apr 2.

National Reference Center for TSE Surveillance, Department of Neurology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Germany.

We discuss relevant aspects in two siblings with a neurodegenerative process of unclear aetiology who developed progressive dementia with global aphasia and hyperoral behaviour at the ages of 39 and 46 years and who died 6 and 5 years after disease onset. The cases were reported to the National Reference Center for TSE Surveillance in Göttingen, Germany. Detailed clinical examinations, CSF, blood samples, and copies of the important diagnostic tests (magnetic resonance imaging, electroencephalogram, laboratory tests) were obtained. Further neuropathological and genetic analyses were performed. Cerebral magnetic resonance imaging of both siblings showed prominent changes in signal intensity, especially in the left medial temporal cortex, but also the hippocampal formation. Neuropathological examination revealed spongiform changes, neuronal loss, and astrocytic gliosis, which are typical in Creutzfeldt-Jakob disease. However, no prion protein deposits were detectable by immunohistochemical analysis, Western blot, or PET blot, though abundant tau protein deposits were observed. A mutation in the coding region of the prion protein genes of both siblings was excluded. A detailed search of the literature revealed no other cases with a similar clinical and neuropathological appearance. While the disease aetiology remains unclear, the findings point to a neurodegenerative process and most likely a genetic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-013-6897-zDOI Listing
July 2013

Low-abundant cerebrospinal fluid proteome alterations in dementia with Lewy bodies.

J Alzheimers Dis 2013 ;34(2):387-97

Department of Neurology, Clinical Dementia Center, Medical Center Georg-August University, Göttingen, Germany.

Dementia with Lewy bodies (DLB) is one of the most common neurodegenerative diseases and shares multiple clinical and neuropathological parallels with Alzheimer's (AD) and Parkinson's disease (PD). A variety of clinical signs are suggestive for the diagnosis, and imaging (βCIT SPECT) contributes substantially to the diagnosis. The study reported here was performed in search for a biomarker in the cerebrospinal fluid (CSF) of these patients. We applied 2D fluorescence difference gel electrophoresis and mass spectrometry to analyze the CSF proteome pattern of DLB patients after depleting twelve high-abundant proteins. The densitometric analysis of 2D gels showed the up- or down-regulation of 44 protein spots. Subsequently, 23 different proteins were identified. The majority is involved in acute phase and immune response. Many of these proteins were previously reported before as being associated with AD or PD, which strongly suggests a molecular cross-talk and may explain clinical and pathological overlap of these disease entities. Among the identified proteins are two highly upregulated proteins-inter alpha trypsin inhibitor heavy chain (ITIH4) and calsyntenin 1-that may have the potential to serve as molecular biomarkers specific for DLB. The identification of DLB-associated proteome changes will help to further understand pathological processes occurring in DLB and may provide future prospects to diagnostic and therapeutic options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-121810DOI Listing
October 2013

Genetic prion disease with codon 196 PRNP mutation: clinical and pathological findings.

Neurobiol Aging 2011 Apr 12;32(4):756.e1-9. Epub 2011 Jan 12.

National Reference Centre for Transmissible Spongiform Encephalopathies, Department of Neurology, Georg-August University, Goettingen, Germany.

Ten percent to 15% of all human transmissible spongiform encephalopathy are characterized by a mutation in prion protein gene (PRNP). They are distinct with respect to clinical signs, disease onset, disease duration, and diagnostic findings. During our surveillance activities in Germany, we identified 7 patients with the rare mutation E196K in PRNP gene, thereof 4 patients belonging to 2 families. The clinical syndromes were characterized by nonspecific and psychiatric symptoms at disease onset and progressed to predominant motor signs. These patients showed a late median disease onset of 71 years and short disease duration of 6.5 months. In absence of family history, they mimicked sporadic Creutzfeldt-Jakob disease (CJD). In clinical tests they were 100% positive for 14-3-3 protein detection in cerebrospinal fluid and less sensitive for magnetic resonance imaging (MRI) and electroencephalogram (EEG) abnormalities. As a secondary magnetic resonance imaging (MRI) abnormality, we have seen conspicuous common involvement of the subcortical white matter in 57%. Four patients underwent autopsy-pathological lesions revealed striking similarity to sporadic Creutzfeldt-Jakob disease but also involvement of the white matter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2010.11.023DOI Listing
April 2011

Amyloid-β 1-42 levels are modified by apolipoprotein E ε4 in Creutzfeldt-Jakob disease in a similar manner as in Alzheimer's disease.

J Alzheimers Dis 2011 ;23(4):717-26

National Reference Center for TSE Surveillance at Department of Neurology, University Medical School, Göttingen, Germany.

The presence of apolipoprotein E (ApoE) ε4 allele is a risk factor for Alzheimer's disease (AD) and associated with a more pronounced reduction of amyloid-β 1-42 (Aβ1-42) in the cerebrospinal fluid (CSF). Because a decrease of Aβ1-42 and increase of tau protein levels, both important biomarkers for AD, are also reported in Creutzfeldt-Jakob disease (CJD), we analyzed if a similar relationship can be observed in this rapid progressive dementia. Our study included 309 patients with sporadic CJD (147 neuropathologically confirmed and 162 probable cases). We analyzed the role of ApoE ε4 in sporadic CJD (sCJD), in particular the influence on the CSF-markers 14-3-3 protein, tau protein, neuron-specific enolase, S100 protein, Aβ1-42, and Aβ1-40. No differences in the ApoE ε4 allele frequency and ApoE genotype distribution between sCJD and published healthy controls were observed. The ApoE ε4 allele had no effect on disease duration or age at onset. We detected a dose-dependent ApoE ε4 effect on the decrease of Aβ1-42 in sCJD. ApoE ε4 carriers with one ApoE ε4 allele showed significantly reduced Aβ1-42 values (p < 0.0001) in comparison with non-carriers. ApoE ε4 allele is not a risk factor for sCJD but modifies the Aβ1-42 levels in CSF in a similar manner as in AD. Based on our results in sCJD patients, we hypothesize that the ApoE ε4 effect on Aβ1-42 values might not be disease-specific.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-2010-101527DOI Listing
March 2012

Codon 129 polymorphism and the E200K mutation do not affect the cellular prion protein isoform composition in the cerebrospinal fluid from patients with Creutzfeldt-Jakob disease.

Eur J Neurosci 2010 Jun 31;31(11):2024-31. Epub 2010 May 31.

National TSE Reference Center, Department of Neurology, Georg-August University Göttingen, Göttingen, Germany.

The cellular prion protein (PrP(c)) is a multifunctional, highly conserved and ubiquitously expressed protein. It undergoes a number of modifications during its post-translational processing, resulting in different PrP(c) glycoforms and truncated PrP(c) fragments. Limited data are available in humans on the expression and cleavage of PrP(c). In this study we investigated the PrP(c) isoform composition in the cerebrospinal fluid from patients with different human prion diseases. The first group of patients was affected by sporadic Creutzfeldt-Jakob disease exhibiting different PrP codon 129 genotypes. The second group contained patients with a genetic form of Creutzfeldt-Jakob disease (E200K). The third group consisted of patients with fatal familial insomnia and the last group comprised cases with the Gerstmann-Sträussler-Scheinker syndrome. We examined whether the PrP codon 129 polymorphism in sporadic Creutzfeldt-Jakob disease as well as the type of prion disease in human patients has an impact on the glycosylation and processing of PrP(c). Immunoblotting analyses using different monoclonal PrP(c) antibodies directed against various epitopes of PrP(c) revealed, for all examined groups of patients, a consistent predominance of the glycosylated PrP(c) isoforms as compared with the unglycosylated form. In addition, the antibody SAF70 recognized a variety of PrP(c) fragments with sizes of 21, 18, 13 and 12 kDa. Our findings indicate that the polymorphisms at PrP codon 129, the E200K mutation at codon 200 or the examined types of human transmissible spongiform encephalopathies do not exert a measurable effect on the glycosylation and processing of PrP(c) in human prion diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1460-9568.2010.07224.xDOI Listing
June 2010

Movement disturbances in the differential diagnosis of Creutzfeldt-Jakob disease.

Mov Disord 2009 Feb;24(3):350-6

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

Movement disturbances are common in dementia disorders and are a central feature of the clinical classification criteria of Creutzfeldt-Jakob disease (CJD). Polymorphism at codon 129 of the prion protein gene is known to determine the clinical picture of CJD. The frequency and characteristics of movement disturbances in other dementing disorders, such as Alzheimer's disease (AD), is barely known and leads to misdiagnoses. We investigated the occurrence and characteristics of movement disturbances in 143 patients neuropathologically confirmed with CJD (n = 100), AD (n = 29), dementia with Lewy bodies (DLB) (n = 7), or other diagnoses (n = 7). All patients had been referred with the differential diagnosis of prion disease. Ataxia and dysmetria were significantly more frequent in CJD than in AD or DLB patients, whereas hypokinesia was up to five times more frequent in AD or DLB (P < 0.05). Using an ordered logistic regression to identify constellations of movement disturbances, the diagnosis of CJD was likely in patients presenting ataxia but not hypokinesia. The reverse situation was statistically associated with AD. Ataxia and cogwheel rigidity were associated with valine-homozygosity and akinesia with methionine-homozygosity in the CJD patients. Our results indicate that the careful assessment of movement disturbances may be helpful in the differential diagnosis of Creutzfeldt-Jakob disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.22253DOI Listing
February 2009

Fatal familial insomnia: Clinical features and early identification.

Ann Neurol 2008 May;63(5):658-61

National TSE Surveillance Reference Center, Department of Neurology, Georg-August University, Göttingen, Germany.

Our aim was to develop a detailed clinical description of fatal familial insomnia in a large patient group with respect to the M129V genotype. Data on 41 German fatal familial insomnia patients were analyzed. Clinical features, 14-3-3 proteins in the cerebrospinal fluid, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, polysomnography, and electroencephalography were studied. Age at disease onset, disease duration, and clinical syndrome varied depending on the codon 129 genotype. Because the sensitivity of the most diagnostic tests is low in fatal familial insomnia, detailed clinical investigation is extremely important. Polysomnography may help to support the diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.21358DOI Listing
May 2008

Brain-derived proteins in the CSF: do they correlate with brain pathology in CJD?

BMC Neurol 2006 Sep 21;6:35. Epub 2006 Sep 21.

National Reference Center for TSE Surveillance, Dept. of Neurology, Georg-August-University Göttingen, Robert-Koch-Str, 40, 37075 Göttingen, Germany.

Background: Brain derived proteins such as 14-3-3, neuron-specific enolase (NSE), S 100b, tau, phosphorylated tau and Abeta1-42 were found to be altered in the cerebrospinal fluid (CSF) in Creutzfeldt-Jakob disease (CJD) patients. The pathogenic mechanisms leading to these abnormalities are not known, but a relation to rapid neuronal damage is assumed. No systematic analysis on brain-derived proteins in the CSF and neuropathological lesion profiles has been performed.

Methods: CSF protein levels of brain-derived proteins and the degree of spongiform changes, neuronal loss and gliosis in various brain areas were analyzed in 57 CJD patients.

Results: We observed three different patterns of CSF alteration associated with the degree of cortical and subcortical changes. NSE levels increased with lesion severity of subcortical areas. Tau and 14-3-3 levels increased with minor pathological changes, a negative correlation was observed with severity of cortical lesions. Levels of the physiological form of the prion protein (PrPc) and Abeta1-42 levels correlated negatively with cortical pathology, most clearly with temporal and occipital lesions.

Conclusion: Our results indicate that the alteration of levels of brain-derived proteins in the CSF does not only reflect the degree of neuronal damage, but it is also modified by the localization on the brain pathology. Brain specific lesion patterns have to be considered when analyzing CSF neuronal proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2377-6-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1592107PMC
September 2006

Clinical features and diagnosis of the MM2 cortical subtype of sporadic Creutzfeldt-Jakob disease.

Arch Neurol 2006 Jun;63(6):876-80

Department of Neurology, Georg-August University, Göttingen, Germany.

Objective: To describe clinical features and diagnostic tests of the MM2 cortical subtype in sporadic Creutzfeldt-Jakob disease.

Methods: Clinical symptoms, magnetic resonance imaging studies, electroencephalograms, and cerebrospinal fluid markers were studied in 12 patients with genetically and neuropathologically verified sporadic Creutzfeldt-Jakob disease. Histological findings were semiquantitatively evaluated.

Results: Compared with classical sporadic Creutzfeldt-Jakob disease, the disease duration was prolonged (median, 14 months). All patients had dementia and early and prominent neuropsychological signs such as spatial disorientation, aphasia, or apraxia. Alzheimer disease was the most frequent initial diagnosis (33%). Increased S100B protein in the cerebrospinal fluid was found in 100%; the 14-3-3 protein test was positive in 91%. Electroencephalograms revealed periodic sharp wave complexes in 42%. T2-weighted magnetic resonance imaging showed basal ganglia hyperintensities in only 1 patient, and cortical hyperintensities were not necessarily present. Severe cortical damage was the most prominent histological feature.

Conclusions: The S100B (100%) and 14-3-3 (91%) protein investigations were the most sensitive diagnostic tests. Prolonged disease duration, dementia as the only typical Creutzfeldt-Jakob disease symptom for a longer time, and low sensitivity of magnetic resonance imaging studies and electroencephalograms make the diagnosis in the MM2 cortical subtype difficult. Therefore, detailed clinical investigation is especially important in this sporadic Creutzfeldt-Jakob disease subtype. We suggest that rapidly progressive dementia with early and prominent neuropsychological deficits in older patients should lead to suspicion of the MM2 cortical subtype even if other neurological deficits are absent. At least some cases of MM2 cortical sporadic Creutzfeldt-Jakob disease may be misdiagnosed as rapidly progressive Alzheimer disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archneur.63.6.876DOI Listing
June 2006

Clinical findings and diagnostic tests in the MV2 subtype of sporadic CJD.

Brain 2006 Sep 23;129(Pt 9):2288-96. Epub 2006 May 23.

Department of Neurology, Georg-August University, Göttingen, Germany.

Atypical clinical course and low sensitivity of established diagnostic tests are the main diagnostic problems in the MV2 subtype of sporadic Creutzfeldt-Jakob disease (sCJD). Clinical symptoms and signs, MRI, EEG and biochemical CSF markers were studied in 26 patients. Histological findings were semiquantitatively evaluated. Compared with typical sCJD, the disease duration was prolonged (median 12 months). Dementia, ataxia and psychiatric symptoms were present in all patients. Extrapyramidal signs were observed in 88%. T2-weighted MRI showed basal ganglia hyperintensities in 90%. Increased thalamic signal intensity was detected in 88% on diffusion-weighted MRI. Increased CSF tau-protein was found in 83%, and the 14-3-3 test was positive in 76%. The EEG revealed periodic sharp wave complexes in only two patients. Kuru plaques, severe thalamic and basal ganglia gliosis and spongiform changes, and neuronal loss in the pulvinar were the prominent histological features. At least one of the three diagnostic tests (MRI, tau- and 14-3-3 protein) supported the clinical diagnosis in all patients. MRI was the most sensitive of the diagnostic tests applied. Thalamic hyperintensities were observed unusually frequently. Prolonged disease duration, early and prominent psychiatric symptoms, absence of typical EEG, thalamic hyperintensities on MRI and relatively low 14-3-3 protein sensitivity may be suspicious for variant CJD. However, distinct sensory symptoms and young age at onset, which are often found in the latter, are not common in the MV2 subtype, and the pulvinar sign was observed in only one case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awl123DOI Listing
September 2006

Clinical course in young patients with sporadic Creutzfeldt-Jakob disease.

Ann Neurol 2005 Oct;58(4):533-43

Neurologische Klinik und Poliklinik der Georg-August-Universität Göttingen, Göttingen, Germany.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease with the greatest incidence occurring in patients between 60 and 70 years old. Younger patients may also be affected. In this study, we used all case material available from 52 patients with sCJD aged 50 years or younger at disease onset, who were identified between 1993 and 2003 in Germany. The objective of this study was to describe the psychiatric and neurological features of these young patients with emphasis on the different codon 129 genotypes and PrP types, and to compare them with elder patients with sCJD and patients with variant CJD. We also gave particular attention to electroencephalogram, magnetic resonance imaging, and 14-3-3 results, as well as to the neuropathological lesion profile. The clinical syndrome in young patients differs from elder patients with CJD with respect to clinical signs, disease duration, technical investigations, and neuropathological lesion profile. The psychiatric symptoms in young patients with sCJD are similar to the psychiatric symptoms expressed by patients with variant CJD; however, in contrast with the variant cases, young patients with sCJD experience development of prominent dementia early in the disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.20568DOI Listing
October 2005