Inga Zerr - Academia.edu (original) (raw)
Papers by Inga Zerr
RESULTS: Cortical abnormalities were present in 70 patients (45%) and were visible in 80% (35/44)... more RESULTS: Cortical abnormalities were present in 70 patients (45%) and were visible in 80% (35/44) of all available DWI examinations. The basal ganglia were affected in 94 patients (60%), in particular in the caudate nucleus; the most sensitive sequences were DWI (64%) and PD-weighted (63%). A thalamic involvement was more frequently diagnosed on PD-weighted images (19%) and DWI (14%) than
European Journal of Epidemiology, 1999
The association between Creutzfeldt–Jakob disease (CJD) and stressful life events was examined in... more The association between Creutzfeldt–Jakob disease (CJD) and stressful life events was examined in a pilot case–control study in Germany. The study sample consisted of 37 CJD cases and 37 controls, both groups were frequency-matched for age and sex. In standardised interviews of close relatives of the cases and the controls, all stressful life events were assessed and subsequently grouped into
Neurobiology of Aging, 2015
Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better i... more Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better insights into changes in brain metabolism. We performed cytokine profiling and measured levels of the cellular prion protein (PrP(C)) in serum and cerebrospinal fluid (CSF) samples from patients with VD and with vascular encephalopathy (VE). Significant changes were observed for interleukin (IL)-1β, IL-4, IL-5, tumor necrosis factor alpha, interferon gamma, granulocyte-colony stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta in serum and for IL-6 and granulocyte macrophage colony-stimulating factor in CSF of VD and VE patients, suggesting that most of immune markers depend on vascular lesions, while only IL-6 was related to dementia. In VD patients, the severity of dementia as defined by the Mini-Mental Status Test or Cambridge Cognitive Examination battery test was significantly correlated with the levels of IL-8 (CSF) and macrophage inflammatory protein 1 beta (serum and CSF). Additionally, in CSF of VD patients, our data revealed a correlation between immune and neurodegenerative marker proteins. Both indicate an association of neuroinflammation and cognitive decline. Levels of PrP(C) were regulated differentially in VD and VE patients compared with Alzheimer's disease patients and controls. Moreover, we observed a significant negative correlation between cytokine levels and PrP(C) in VD patients in CSF and serum, as well as a correlation between PrP(C) expression with levels of neurodegenerative marker proteins in CSF (in VD and VE patients). Our data suggest that immunological modifiers play a role in VD and VE patients and provide evidence for an association of PrP(C) with immune and neurodegenerative markers.
Experimental neurology, Jan 27, 2015
Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clari... more Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clarified a PrP(c)-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion knockout mice (Prnp(0/0)) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrP(c). Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp(0/0) knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line. While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp(0/0) primary cortical neurons with concurrent less hypoxia-induced damage in the forme...
Molecular Neurobiology, 2015
At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker te... more At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test. Hereby, 14-3-3 protein expression was quantitatively analyzed in CSF of 231 sCJD and 2035 control patients. We obtained excellent sensitivity/specificity values of 88 and 96 % that are comparable to the established Western blot method. Since standard protocols and preanalytical sample handling have become more important in routine diagnostic, we investigated in a further step the reproducibility and stability of 14-3-3 as a biomarker for human prion diseases. Ring trial data from 2009 to 2013 revealed an increase of Fleiss' kappa from 0.51 to 0.68 indicating an improving reliability of 14-3-3 protein detection. The stability of 14-3-3 protein under short-term and long-term storage conditions at various temperatures and after repeated freezing/thawing cycles was confirmed. Contamination of CSF samples with blood appears likely to be an important factor at a concentration of more than 2500 erythrocytes/μL. Hemolysis of erythrocytes with significant release of 14-3-3 protein started after 2 days at room temperature. We first define clear standards for the sample handling, short- and long-term storage of CSF samples as well as the handling of blood- contaminated samples which may result in artificially elevated CSF levels of 14-3-3.
PloS one, 2014
We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJ... more We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Ge...
Molecular neurobiology, 2015
Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of s... more 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...
American journal of neurodegenerative disease, 2014
Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by great phenotypic variability regard... more Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by great phenotypic variability regarding clinical course and neuropathology. The most prominent disease modifiers are a polymorphism in Codon 129 of the prion protein gene and conformational variations of the misfolded prion protein. The cellular form of the prion protein restricts replication of viruses and may be involved in viral host defense, and viral infections influence the presentation and neuropathology in prion diseased mice. We investigated the occurrence of reactivated persistent viral infections of the brain in brain tissue samples of 25 sCJD patients. No evidence of reactivated JCV and CMV infections could be detected. This suggests that JCV and CMV infections are not reactivated as consequence of prion disease and do not act as disease modifiers in sCJD.
Acta neurologica Belgica, 2011
Creutzfeld-Jacob disease (CJD) is a degenerative, invariably fatal brain disorder. Multiple scler... more Creutzfeld-Jacob disease (CJD) is a degenerative, invariably fatal brain disorder. Multiple sclerosis (MS) is a chronic, potentially disabling, immune-mediated inflammatory demyelinating disease of the central nervous system. Here, we report a 50-year-old woman who, two years after the diagnosis of relapsing remitting MS, developed altered consciousness, dystonic posture of the left hand and myoclonic jerks. Repeated brain MRI showed hyperintensities on T2 sequences in basal ganglia bilaterally and diffusion restriction in these areas, and, since typical EEG and CSF features were present, the diagnosis of CJD was made. To the best of our knowledge, this is the first report of a glatiramer acetate-treated MS patient who developed sporadic CJD. This combination is interesting in the light of recent data suggesting that CJD and MS may share similar mechanisms of "molecular mimicry" and autoimmunity. This case also emphasizes the importance of critically assessing every new sy...
Objective: To analyze whether a positive family history of dementia (PFHD) is more common in spor... more Objective: To analyze whether a positive family history of dementia (PFHD) is more common in sporadic CJD (sCJD) than in healthy/population controls and to study associated risk factors. Patients/methods: Six hundred and eighty-five sCJD patients and 659 sex-/age-matched controls were included. A PFHD in parents/grandparents/siblings was evaluated. The PRNP M129V polymorphism and ApoE genotype in sCJD with/without PFHD were determined by PCR. Results: PFHD was found in 12.1% of sCJD patients and 5.6% of controls (p < 0.001). No significant difference in M129V polymorphism was found between sCJD with and without PFHD. Thirty-six percent of sCJD patients with PFHD, 26% without PFHD and 19% of healthy controls had at least one ApoE4 allele. Compared to controls, ApoE4 allele frequency (p = 0.005) and proportion of ApoE4 allele carriers (p = 0.019) were significantly higher in sCJD with PFHD. Interpretation: A higher frequency of the ApoE4 allele in sCJD with a PFHD could be indicative of an additional risk factor in CJD.
Journal of Neurology Neurosurgery and Psychiatry, 2001
OBJECTIVESTo describe the clinical presentation of patients with Alzheimer's disease (AD) or ... more OBJECTIVESTo describe the clinical presentation of patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) who were suspected of having Creutzfeldt-Jakob disease (CJD) and to investigate whether current clinical diagnostic criteria cover these atypical forms of AD and DLB.METHODSBrains from necropsy were examined for the diagnosis of CJD at the German reference centre for spongiform encephalopathies. Symptoms and
Brain, 2002
Summary The pathogenesis underlying the typical findings in Creutzfeldt-Jakob disease (CJD) such ... more Summary The pathogenesis underlying the typical findings in Creutzfeldt-Jakob disease (CJD) such as periodic EEG changes or myoclonus is not fully understood. The thalamus possesses a high density of inhibitory neurones and serves as a crucial pacemaker of rhythmic EEG activity. As inhibitory neurones expressing parvalbumin (PV) are reduced in the cerebral cortex and hippocam- pus in sporadic CJD (sCJD),
Journal of Alzheimer's disease : JAD, 2012
The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD)... more The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease.
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2014
The objective of this study was to investigate potential associations of Alzheimer's disease ... more The objective of this study was to investigate potential associations of Alzheimer's disease risk single nucleotide polymorphisms (SNP) with disease progression. SNP in ACE, ApoE, BIN1, CLU, CR1, CST3, EXOC3L2, GWA14q32.13, IL8, LDLR, PICALM, and TNK1 were determined in 40 Alzheimer's disease patients who were observed for 2 to 3 years. Annual Mini Mental State Examination (MMSE) loss was used as the outcome parameter in multiple regression analyses. Regarding a CR1 SNP (rs3818361) G-allele carriers featured faster declines (approximately 3 MMSE points per year). To summarize, in addition to being a risk factor for Alzheimer's disease development, a CR1 SNP appears to be associated with higher rates of medium-term disease progression. Therefore, it may serve as a prognostic marker (among others) and may aid in differentiating slow from fast progressors early in the disease course.
Journal of Alzheimer's disease : JAD, 2015
Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal ... more Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a potential biomarker, which would be predictive of cognitive, functional, or motor decline, we analyzed CSF apolipoprotein E (ApoE) levels of AD patients in this regard. Subjects with newly diagnosed AD enrolled into an observational study were followed up longitudinally. Neuropsychological testing and physical examination were performed annually. In a sub-cohort of patients, where baseline CSF ApoE concentration values were available, multiple regression analyses were used to determine possible associations of CSF ApoE concentration and speed of decline on different cognitive, functional, and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusting for possible confounders. No association of CSF ApoE levels and speed of decline on the various scales could be established (p = 0.09 to 0.88). Neverthe...
Neurobiology of Aging, 2015
The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic mar... more The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), MV (p = 0.004), and VV (p = 0.001) genotype. Receiver operating characteristic analyses showed values of area under the curve of 0.76-0.80 for the different genotypes indicating a good diagnostic validity of the test. Total tau can be used as a diagnostic test for the assessment of prion protein type when codon 129 genotype is known. It provides valuable information for physicians and next of kin about the further course of disease.
Prion, 2014
Recently, PrP(c) has been linked to AD pathogenesis. Second, a relation of PrP(c) plasma levels w... more Recently, PrP(c) has been linked to AD pathogenesis. Second, a relation of PrP(c) plasma levels with cognitive status and decline of healthy elderly subjects has been reported. Therefore, we hypothesized baseline plasma levels of PrP(c) to be associated with AD progression in cognitive and functional domains. AD patients (n = 84) were included into an observational study at time of diagnosis. Baseline plasma PrP(c) levels were determined. Decline was assessed annually (mean follow-up time 3 years) with the aid of different standardized tests (MMSE, iADL, bADL, GDS, UPDRSIII). Multiple regression analyses were used to uncover potential associations between decline and PrP(c) levels. No association of PrP(c) and decline could be established. Presence of diabetes mellitus was linked to slower deterioration. Intake of neuroleptic drugs or memantine was associated with faster progression. Plasma PrP(c) at baseline could not be shown to be related to AD progression in this study. An interesting association of diabetes mellitus and decline warrants further investigation.
BMC neurology, 2006
Brain derived proteins such as 14-3-3, neuron-specific enolase (NSE), S 100b, tau, phosphorylated... more 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. 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. 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 prote...
Neurobiology of Aging, 2015
Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfo... more Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;100, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;500, or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a…
Acta Neuropathologica, 2007
We report on a novel subtype of Creutzfeldt–Jakob disease with a single proteinase K-resistant pr... more We report on a novel subtype of Creutzfeldt–Jakob disease with a single proteinase K-resistant prion protein fragment of about 6 kDa in Western blots of brain homogenates. Clinically this patient showed a progressive spastic disorder and dementia over 3 years. No mutation of the prion protein gene was found. Since this patient had received a blood transfusion, an iatrogenic cause, albeit unlikely,
RESULTS: Cortical abnormalities were present in 70 patients (45%) and were visible in 80% (35/44)... more RESULTS: Cortical abnormalities were present in 70 patients (45%) and were visible in 80% (35/44) of all available DWI examinations. The basal ganglia were affected in 94 patients (60%), in particular in the caudate nucleus; the most sensitive sequences were DWI (64%) and PD-weighted (63%). A thalamic involvement was more frequently diagnosed on PD-weighted images (19%) and DWI (14%) than
European Journal of Epidemiology, 1999
The association between Creutzfeldt–Jakob disease (CJD) and stressful life events was examined in... more The association between Creutzfeldt–Jakob disease (CJD) and stressful life events was examined in a pilot case–control study in Germany. The study sample consisted of 37 CJD cases and 37 controls, both groups were frequency-matched for age and sex. In standardised interviews of close relatives of the cases and the controls, all stressful life events were assessed and subsequently grouped into
Neurobiology of Aging, 2015
Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better i... more Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better insights into changes in brain metabolism. We performed cytokine profiling and measured levels of the cellular prion protein (PrP(C)) in serum and cerebrospinal fluid (CSF) samples from patients with VD and with vascular encephalopathy (VE). Significant changes were observed for interleukin (IL)-1β, IL-4, IL-5, tumor necrosis factor alpha, interferon gamma, granulocyte-colony stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta in serum and for IL-6 and granulocyte macrophage colony-stimulating factor in CSF of VD and VE patients, suggesting that most of immune markers depend on vascular lesions, while only IL-6 was related to dementia. In VD patients, the severity of dementia as defined by the Mini-Mental Status Test or Cambridge Cognitive Examination battery test was significantly correlated with the levels of IL-8 (CSF) and macrophage inflammatory protein 1 beta (serum and CSF). Additionally, in CSF of VD patients, our data revealed a correlation between immune and neurodegenerative marker proteins. Both indicate an association of neuroinflammation and cognitive decline. Levels of PrP(C) were regulated differentially in VD and VE patients compared with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease patients and controls. Moreover, we observed a significant negative correlation between cytokine levels and PrP(C) in VD patients in CSF and serum, as well as a correlation between PrP(C) expression with levels of neurodegenerative marker proteins in CSF (in VD and VE patients). Our data suggest that immunological modifiers play a role in VD and VE patients and provide evidence for an association of PrP(C) with immune and neurodegenerative markers.
Experimental neurology, Jan 27, 2015
Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clari... more Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clarified a PrP(c)-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion knockout mice (Prnp(0/0)) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrP(c). Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp(0/0) knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line. While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp(0/0) primary cortical neurons with concurrent less hypoxia-induced damage in the forme...
Molecular Neurobiology, 2015
At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker te... more At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test. Hereby, 14-3-3 protein expression was quantitatively analyzed in CSF of 231 sCJD and 2035 control patients. We obtained excellent sensitivity/specificity values of 88 and 96 % that are comparable to the established Western blot method. Since standard protocols and preanalytical sample handling have become more important in routine diagnostic, we investigated in a further step the reproducibility and stability of 14-3-3 as a biomarker for human prion diseases. Ring trial data from 2009 to 2013 revealed an increase of Fleiss&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; kappa from 0.51 to 0.68 indicating an improving reliability of 14-3-3 protein detection. The stability of 14-3-3 protein under short-term and long-term storage conditions at various temperatures and after repeated freezing/thawing cycles was confirmed. Contamination of CSF samples with blood appears likely to be an important factor at a concentration of more than 2500 erythrocytes/μL. Hemolysis of erythrocytes with significant release of 14-3-3 protein started after 2 days at room temperature. We first define clear standards for the sample handling, short- and long-term storage of CSF samples as well as the handling of blood- contaminated samples which may result in artificially elevated CSF levels of 14-3-3.
PloS one, 2014
We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJ... more We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Ge...
Molecular neurobiology, 2015
Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of s... more 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...
American journal of neurodegenerative disease, 2014
Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by great phenotypic variability regard... more Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by great phenotypic variability regarding clinical course and neuropathology. The most prominent disease modifiers are a polymorphism in Codon 129 of the prion protein gene and conformational variations of the misfolded prion protein. The cellular form of the prion protein restricts replication of viruses and may be involved in viral host defense, and viral infections influence the presentation and neuropathology in prion diseased mice. We investigated the occurrence of reactivated persistent viral infections of the brain in brain tissue samples of 25 sCJD patients. No evidence of reactivated JCV and CMV infections could be detected. This suggests that JCV and CMV infections are not reactivated as consequence of prion disease and do not act as disease modifiers in sCJD.
Acta neurologica Belgica, 2011
Creutzfeld-Jacob disease (CJD) is a degenerative, invariably fatal brain disorder. Multiple scler... more Creutzfeld-Jacob disease (CJD) is a degenerative, invariably fatal brain disorder. Multiple sclerosis (MS) is a chronic, potentially disabling, immune-mediated inflammatory demyelinating disease of the central nervous system. Here, we report a 50-year-old woman who, two years after the diagnosis of relapsing remitting MS, developed altered consciousness, dystonic posture of the left hand and myoclonic jerks. Repeated brain MRI showed hyperintensities on T2 sequences in basal ganglia bilaterally and diffusion restriction in these areas, and, since typical EEG and CSF features were present, the diagnosis of CJD was made. To the best of our knowledge, this is the first report of a glatiramer acetate-treated MS patient who developed sporadic CJD. This combination is interesting in the light of recent data suggesting that CJD and MS may share similar mechanisms of "molecular mimicry" and autoimmunity. This case also emphasizes the importance of critically assessing every new sy...
Objective: To analyze whether a positive family history of dementia (PFHD) is more common in spor... more Objective: To analyze whether a positive family history of dementia (PFHD) is more common in sporadic CJD (sCJD) than in healthy/population controls and to study associated risk factors. Patients/methods: Six hundred and eighty-five sCJD patients and 659 sex-/age-matched controls were included. A PFHD in parents/grandparents/siblings was evaluated. The PRNP M129V polymorphism and ApoE genotype in sCJD with/without PFHD were determined by PCR. Results: PFHD was found in 12.1% of sCJD patients and 5.6% of controls (p < 0.001). No significant difference in M129V polymorphism was found between sCJD with and without PFHD. Thirty-six percent of sCJD patients with PFHD, 26% without PFHD and 19% of healthy controls had at least one ApoE4 allele. Compared to controls, ApoE4 allele frequency (p = 0.005) and proportion of ApoE4 allele carriers (p = 0.019) were significantly higher in sCJD with PFHD. Interpretation: A higher frequency of the ApoE4 allele in sCJD with a PFHD could be indicative of an additional risk factor in CJD.
Journal of Neurology Neurosurgery and Psychiatry, 2001
OBJECTIVESTo describe the clinical presentation of patients with Alzheimer's disease (AD) or ... more OBJECTIVESTo describe the clinical presentation of patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) who were suspected of having Creutzfeldt-Jakob disease (CJD) and to investigate whether current clinical diagnostic criteria cover these atypical forms of AD and DLB.METHODSBrains from necropsy were examined for the diagnosis of CJD at the German reference centre for spongiform encephalopathies. Symptoms and
Brain, 2002
Summary The pathogenesis underlying the typical findings in Creutzfeldt-Jakob disease (CJD) such ... more Summary The pathogenesis underlying the typical findings in Creutzfeldt-Jakob disease (CJD) such as periodic EEG changes or myoclonus is not fully understood. The thalamus possesses a high density of inhibitory neurones and serves as a crucial pacemaker of rhythmic EEG activity. As inhibitory neurones expressing parvalbumin (PV) are reduced in the cerebral cortex and hippocam- pus in sporadic CJD (sCJD),
Journal of Alzheimer's disease : JAD, 2012
The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD)... more The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease.
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2014
The objective of this study was to investigate potential associations of Alzheimer's disease ... more The objective of this study was to investigate potential associations of Alzheimer's disease risk single nucleotide polymorphisms (SNP) with disease progression. SNP in ACE, ApoE, BIN1, CLU, CR1, CST3, EXOC3L2, GWA14q32.13, IL8, LDLR, PICALM, and TNK1 were determined in 40 Alzheimer's disease patients who were observed for 2 to 3 years. Annual Mini Mental State Examination (MMSE) loss was used as the outcome parameter in multiple regression analyses. Regarding a CR1 SNP (rs3818361) G-allele carriers featured faster declines (approximately 3 MMSE points per year). To summarize, in addition to being a risk factor for Alzheimer's disease development, a CR1 SNP appears to be associated with higher rates of medium-term disease progression. Therefore, it may serve as a prognostic marker (among others) and may aid in differentiating slow from fast progressors early in the disease course.
Journal of Alzheimer's disease : JAD, 2015
Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal ... more Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a potential biomarker, which would be predictive of cognitive, functional, or motor decline, we analyzed CSF apolipoprotein E (ApoE) levels of AD patients in this regard. Subjects with newly diagnosed AD enrolled into an observational study were followed up longitudinally. Neuropsychological testing and physical examination were performed annually. In a sub-cohort of patients, where baseline CSF ApoE concentration values were available, multiple regression analyses were used to determine possible associations of CSF ApoE concentration and speed of decline on different cognitive, functional, and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusting for possible confounders. No association of CSF ApoE levels and speed of decline on the various scales could be established (p = 0.09 to 0.88). Neverthe...
Neurobiology of Aging, 2015
The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic mar... more The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), MV (p = 0.004), and VV (p = 0.001) genotype. Receiver operating characteristic analyses showed values of area under the curve of 0.76-0.80 for the different genotypes indicating a good diagnostic validity of the test. Total tau can be used as a diagnostic test for the assessment of prion protein type when codon 129 genotype is known. It provides valuable information for physicians and next of kin about the further course of disease.
Prion, 2014
Recently, PrP(c) has been linked to AD pathogenesis. Second, a relation of PrP(c) plasma levels w... more Recently, PrP(c) has been linked to AD pathogenesis. Second, a relation of PrP(c) plasma levels with cognitive status and decline of healthy elderly subjects has been reported. Therefore, we hypothesized baseline plasma levels of PrP(c) to be associated with AD progression in cognitive and functional domains. AD patients (n = 84) were included into an observational study at time of diagnosis. Baseline plasma PrP(c) levels were determined. Decline was assessed annually (mean follow-up time 3 years) with the aid of different standardized tests (MMSE, iADL, bADL, GDS, UPDRSIII). Multiple regression analyses were used to uncover potential associations between decline and PrP(c) levels. No association of PrP(c) and decline could be established. Presence of diabetes mellitus was linked to slower deterioration. Intake of neuroleptic drugs or memantine was associated with faster progression. Plasma PrP(c) at baseline could not be shown to be related to AD progression in this study. An interesting association of diabetes mellitus and decline warrants further investigation.
BMC neurology, 2006
Brain derived proteins such as 14-3-3, neuron-specific enolase (NSE), S 100b, tau, phosphorylated... more 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. 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. 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 prote...
Neurobiology of Aging, 2015
Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfo... more Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;100, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;500, or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a…
Acta Neuropathologica, 2007
We report on a novel subtype of Creutzfeldt–Jakob disease with a single proteinase K-resistant pr... more We report on a novel subtype of Creutzfeldt–Jakob disease with a single proteinase K-resistant prion protein fragment of about 6 kDa in Western blots of brain homogenates. Clinically this patient showed a progressive spastic disorder and dementia over 3 years. No mutation of the prion protein gene was found. Since this patient had received a blood transfusion, an iatrogenic cause, albeit unlikely,