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Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity.

Das Konzept der Protein-Fehlfaltung als Ursache einer Neurodegeneration wie der Creutzfeldt-Jakob-Erkrankung (CJK) wurde bei der Gruppe der Prionerkrankungen erstmalig beschrieben. Obwohl diese als vergleichsweise selten und exotisch betrachtet werden, hatten sie letztlich einen grosen Stellenwert fur das Verstandnis pathogenetischer Mechanismen bei anderen neurodegenerativen Erkrankungen.

Background and purpose: To establish radiological features in the atypical MV2 subtype of sCJD compared with the classical MM1 subtype, as well as region- and sequence-dependent inter-observer correlation. Methods: MRI hyperintensity of basal ganglia (BG), cortex and thalamus was evaluated in 31 MM1 and 32 MV2 patients. Each MR scan was analyzed independently by two neuroradiologists blinded to PRNP genotype/prion protein type. Results: Cumulative T2-sensitivity for BG hyperintensity was higher in the MV2 subtype (84% for both observers versus 61% in observer 1/42% in observer 2 in MM1 patients). Significant inter-observer agreement was found for BG and thalamus on T2, FLAIR, PD and DWI, but for cortex only on DWI. Thalamic changes were significantly more frequent in MV2 than in MM1 patients (cumulative sensitivity 86% vs. 12.5% on DWI). Discussion: The high frequency of thalamic hyperintensity in the MV2 subtype allowed differentiation from MM1 patients. Good inter-observer agreement was found for BG and thalamus in all sequences. DWI showed the highest inter-observer correlation independent of the investigated brain region and was therefore not only highly sensitive but also relatively independent of investigator bias. Since inter-observer correlation for cortical hyperintensity in T2, FLAIR and PD is relatively low, the cortical changes should not be over-interpreted with these sequences.

BACKGROUND AND PURPOSE: High cortical signal intensity on diffusion-weighted (DW) or fluid-attenuated inversion recovery (FLAIR) images is increasingly described in sporadic Creutzfeldt-Jakob disease (sCJD). The aim of this study was to assess the extent and location of high cortical signal intensity, to investigate whether DW or FLAIR is superior in showing changes in cortical signal intensity, and to find out whether the distribution of the signal intensity changes is random or follows a common pattern. MATERIALS AND METHODS: We analyzed FLAIR and DW MR imaging scans of 39 patients with sCJD for hyperintense cortical signal intensity. We compared the sensitivity of the DW and FLAIR scans. We correlated the extent and location of the cortical signal intensity changes with concomitant changes in deep gray matter and the genotype of codon 129 of the prion protein gene. RESULTS: There was high signal intensity in the insula, the cingulate gyrus, and the superior frontal gyrus in 95%. The cortical areas near the midline also frequently showed the abnormal signal intensity (precuneus 87%, paracentral lobe 77%). The precentral and postcentral gyri were affected less frequently (41% and 28%, respectively). The DW MR imaging showed the cortical changes more effectively than FLAIR. There was no correlation between the distribution of changes and additional signal alterations in deep gray matter or the genotype of codon 129. CONCLUSION: The distribution of cortical signal intensity abnormalities in patients with sCJD follows a common pattern, affecting mainly the cortical areas near the midline, the insula, cingulum, and the superior frontal cortex. DW imaging is superior to FLAIR in the detection of cortical high signal intensity.

Aside from variation in the prion protein gene, genetic risk factors for sporadic Creutzfeldt-Jakob disease (sCJD) remain elusive. Given emerging evidence implicating mitochondrial dysfunction in the pathogenesis of the disorders, we studied the role of inherited mitochondrial DNA (mtDNA) variation in a 2255 sporadic prion disease cases and 3768 controls. Our analysis indicates that inherited mtDNA variation does not have a major role in the risk of developing the disorder, adding to recent nuclear genome wide association studies that failed to define additional genetic risk loci.

Background: Recently, six molecular subtypes of sporadic CJD (sCJD) have been identified showing differences regarding the disease course, neuropathologic lesion patterns, and sensitivity to diagnostic tools. Only isolated cases of the rare VV1 type have been reported so far. Objective: To describe the clinical characteristics and neuropathologic lesion profiles in nine cases. Methods: In the years 1993 until late 2003, 571 definite neuropathologically confirmed cases of sporadic CJD were identified in Germany. Of these, nine were homozygous for valine and displayed type 1 of the pathologic PrP Sc in the brain (VV1 type). Results: The authors describe eight men and one woman belonging to the VV1 type. All patients were relatively young at disease onset (median 44 years vs 65 years in all sCJD) with prolonged disease duration (median 21 months vs 6 months in all sCJD). During the initial stages, their main clinical signs were personality changes and slowly progressive dementia as well as focal neurologic deficits. None of the nine VV1 patients had periodic sharp-wave complexes (PSWCs) in the EEG. Only two out of seven displayed the typical signal increase of the basal ganglia on MRI, whereas signal increase of the cortex was seen in all patients. The 14-3-3 protein levels were elevated in CSF in all cases tested. Conclusions: The clinical diagnosis of the VV1 type of sCJD can be best supported by the 14-3-3 test and cortical signal increase on MRI. Because of the young age at onset vCJD is sometimes suspected as a differential diagnosis. MRI plays an important role in differentiating these two disease types and should be performed early during the disease course.

Objective: To assess if clinical features, prion protein codon 129, and molecular subtype correlate with MRI basal ganglia hyperintensity in sporadic Creutzfeldt-Jakob disease (CJD). Methods: The authors studied 219 patients including 153 confirmed CJD cases for their neurologic symptoms and MRI findings. The MRI was assessed by a blinded investigator for the presence of high signal intensity on T2-weighted images in the basal ganglia. Results: Patients with basal ganglia high signal on T2-weighted images were more likely to present with rapid progressive dementia in an early stage and shorter disease duration (median 6.7 months and 8.6 months). Surprisingly, among the CJD cases, patients without signal increase of the basal ganglia were shown to have a higher frequency of extrapyramidal disturbances (82% vs 70%). More striking differences were found for symptoms such as depression and sensory disturbances, which were more frequent among cases without signal increase. MRI was more likely to be diagnostic in patients with MV2 molecular subtype. Conclusions: Selected clinical and pathologic features correlate with the presence of basal ganglia high signal on T2-weighted MRI in patients with definite or probable CJD.

Bei den menschlichen Prionerkrankungen lassen sich neben der sporadischen Form der Creutzfeldt-Jakob-Krankheit auch die neue Variante und iatrogene Formen abgrenzen. Zusatzlich sind auch hereditare Formen zu beobachten, als Sonderfall einer von Mensch zu Mensch ubertragenen Form ist Kuru von Bedeutung. Der vorliegende Beitrag be-schreibt die unterschiedlichen klinischen und neuropathologischen Besonderheiten der verschiedenen Varianten der spongiformen Enzephalopathien, deren Abgrenzung weiterhin schwierig bleibt. Zusatzlich werden die Erweiterungen der diagnostischen Moglichkeiten beschrieben, die es ermoglicht haben, dass die Diagnosestellung haufig schon zu Lebzeiten der Patienten er-folgen kann und nicht mehr nur autoptisch zu sichern ist.

Two-dimensional polyacrylamide gel electrophoresis of CSF has been used in the diagnosis of Creutzfeldt-Jakob disease (CJD). One of the two diagnostic protein spots was identified as isoform(s) of the 14-3-3 family of abundant brain proteins. This has led to the development of one-dimensional 14-3-3 sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot, which is currently used to support the diagnosis of CJD. In the present study employing western blot analysis, we have identified the panel of 14-3-3 isoforms that appear in the CSF of 10 patients with CJD compared with 10 patients with other dementias. The results clearly show that the 14-3-3 isoforms beta, gamma, epsilon, and eta are present in the CSF of patients with CJD and can be used to differentiate other dementias. 14-3-3eta also gave a baseline signal in all patients with other dementias, including six patients with Alzheimer's disease. The presence of 14-3-3eta in the CSF of a patient with herpes simplex encephalitis was particularly noteworthy. This study has determined that isoform-specific 14-3-3 antibodies against beta, gamma, and epsilon should be considered for the neurochemical differentiation of CJD from other neurodegenerative diseases.

OBJECTIVES To describe the clinical presentation of patients with Alzheimer9s 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. METHODS Brains from necropsy were examined for the diagnosis of CJD at the German reference centre for spongiform encephalopathies. Symptoms and signs in patients with suspected CJD in whom necropsy showed AD (n=19) or DLB (n=12) were analysed. Their data were compared with a group of patients with CJD (n=25) to determine overlapping and discriminating clinical features. All patients were classified according to clinical diagnostic criteria for CJD, AD, and DLB. RESULTS Demented patients were suspected of having CJD if disease was rapidly progressing and/or focal neurological signs appeared and/or an EEG showed sharp wave complexes. Myoclonus and limb rigidity were the most common neurological signs in all three dementias. DLB was not suspected in any patient, although patients with DLB showed parkinsonism (58%) and fluctuations (58%). Periodic sharp wave complexes (PSWCs) in EEG typical of CJD were found in five patients with AD and one patient with DLB. 14–3–3 Protein in CSF was detected in 20 patients with CJD, in two patients with AD, but not in any patient with DLB. Although most patients with DLB or AD met the clinical criteria for their respective diagnosis (74% and 90%), they also fulfilled criteria for CJD (42% and 58%). CONCLUSIONS In patients with rapidly progressive dementia and focal neurological signs, CJD should be the first line diagnosis. Facing the triad dementia, myoclonus, and rigidity, AD should be considered if the disease course is longer and DLB is the differential diagnosis if parkinsonism or fluctuations are present. Findings on EEG or CSF typical of CJD do not exclude AD or DLB.

Seit Entdeckung ihrer Ubertragbarkeit findet die Creutzfeldt-Jakob-Krankheit zunehmendes Interesse in der Offentlichkeit. Die BSE-Epidemie (bovine spongiforme Enzephalitis) und die Befurchtung, diese Rinderkrankheit konne durch Verzehr von infizierten Rinderprodukten auf den Menschen ubergehen, schuf die Voraussetzungen fur epidemiologische Untersuchungen. Das Auftreten einer neuen Variante der Creutzfeldt-Jakob-Krankheit erharteten den Zusammenhang mit BSE. Obwohl beide Formen zu den Prionenerkrankungen gehoren, unterscheidet sich die sporadische Form von der neuen Variante im klinischen und neuropathologischen Bild. Wahrend die neue Variante bisher uberwiegend bei jungen Patienten beobachtet wurde, tritt die klassische sporadische Form vorwiegend im 6.–7. Lebensjahrzehnt auf. Die Haufigkeit der sporadischen Creutzfeldt-Jakob-Krankheit betragt in Deutschland etwa ein Fall pro Jahr pro Million Einwohner. Die neue Variante wurde dagegen bisher fast ausschlieslich in Grosbritannien beobachtet.

The causes and geographic distribution of 267 cases of iatrogenic Creutzfeldt-Jakob disease (CJD) are here updated at the millennium. Small numbers of still-occurring cases result from disease onsets after longer and longer incubation periods following infection by cadaveric human growth hormone or dura mater grafts manufactured and distributed before the mid-1980s. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4% in different countries, and acquisition from dura mater varies between 0.02 and 0.05% in Japan (where most cases occurred). Incubation periods can extend up to 30 years, and cerebellar onsets predominate in both hormone and graft recipients (in whom the site of graft placement had no effect on the clinical presentation). Homozygosity at codon 129 of the PRNP gene is over-represented in both forms of disease; it has no effect on the incubation period of graft recipients, but may promote shorter incubation periods in hormone cases. Knowledge about potential high-risk sources of contamination gained during the last quarter century, and the implementation of methods to circumvent them, should minimize the potential for iatrogenic contributions to the current spectrum of CJD.

A definite diagnosis of prion diseases such as Creutzfeldt–Jakob disease (CJD) relies on the detection of pathological prion protein (PrP Sc ). However, no test for PrP Sc in cerebrospinal fluid (CSF) has been available thus far. Based on a setup for confocal dual-color fluorescence correlation spectroscopy, a technique suitable for single molecule detection, we developed a highly sensitive detection method for PrP Sc . Pathological prion protein aggregates were labeled by specific antibody probes tagged with fluorescent dyes, resulting in intensely fluorescent targets, which were measured by dual-color fluorescence intensity distribution analysis in a confocal scanning setup. In a diagnostic model system, PrP Sc aggregates were detected down to a concentration of 2 pM PrP Sc , corresponding to an aggregate concentration of approximately 2 fM, which was more than one order of magnitude more sensitive than Western blot analysis. A PrP Sc -specific signal could also be detected in a number of CSF samples from patients with CJD but not in control samples, providing the basis for a rapid and specific test for CJD and other prion diseases. Furthermore, this method could be adapted to the sensitive detection of other disease-associated amyloid aggregates such as in Alzheimer's disease.

Objectives: Decreased levels of Aβ 1-42 are found in CSF of patients with AD. Because early stages of Creutzfeldt-Jakob disease (CJD) and AD share several clinical features, we investigated Aβ 1-42 levels in CSF of these groups, inferring that this might give additional help in differentiating patients with CJD from AD patients. Methods: We investigated 27 patients with CJD, 14 patients with AD, 19 patients with other dementias, and 20 nondemented controls (NDC) for Aβ 1-42 in CSF. Twenty-four of the 27 CJD patients were neuropathologically verified. All the neuropathologically verified patients presented with a type 1 prion protein pattern. CJD patients were all homozygous for methionine at codon 129. Except in five CJD patients, no β-amyloid plaques were seen. Additionally, APOE status was determined in patients with CJD. Results: Levels of Aβ 1-42 in CSF were decreased in patients with AD as well as in CJD. Levels of Aβ 1-42 in CSF of patients with CJD and AD were significantly different from the other dementia and NDC groups. There was no substantial difference between the CJD and AD groups ( p = 0.66). Decreased levels of Aβ 1-42 did not correlate with the APOE e4 load in patients with CJD. Conclusion: Low levels of Aβ 1-42 in CSF do not exclude a diagnosis of CJD. Decreased levels of Aβ 1-42 in CSF can occur without β-amyloid plaque formation in the brain. However, the underlying mechanism of this phenomenon must be elucidated.

This paper describes a prospective follow-up of 364 patients initially notified as suspected Creutzfeldt-Jakob disease to a Surveillance Unit in Göttingen, Germany. Six patients were diagnosed as having genetic prion disease by blood analysis and were excluded from the study. After examination and review of the remaining 358, 193 were classified as probable Creutzfeldt-Jakob disease. However, autopsy revealed that five of the 193 did not have Creutzfeldt-Jakob disease (four cases, Alzheimer's disease; one case, cerebral lymphoma). Of the 54 patients classified as possible Creutzfeldt-Jakob disease, 10 had another diagnosis made at autopsy. Two of the 111 cases originally classified as having other diseases were found to have Creutzfeldt-Jakob disease on autopsy. Autopsy evidence, together with follow-up of the patients still living and those who died without autopsy, revealed a broad range of other diagnoses. In the younger age groups, the commonest were chronic inflammatory diseases including Hashimoto encephalitis, whilst rapidly progressive Alzheimer's disease was most common in the older age groups. The presence of 14-3-3 protein in the CSF discriminated better between Creutzfeldt-Jakob disease and other rapidly progressive dementias than did the EEG pattern or the MRI. The inclusion of this CSF protein in the criteria of Masters and colleagues (Ann Neurol 1979; 5: 177-88) improves the accuracy and confidence in the clinical diagnosis of Creutzfeldt-Jakob disease.

ZusammenfassungWir berichten über einen 61jährigen Patienten mit progredientem dementieilen Syndrom, der unter der Verdachtsdiagnose einer Demenz vom Alzheimer-Typ (DAT) zur Hirn-SPECT-Untersuchung mit Tc-99m-Bicisat (ECD) vorgestellt wurde. Zum Untersuchungszeitpunkt bestanden neben dem Vollbild einer Demenz eine ausgeprägte Apraxie und Aphasie bei unspezifischen Veränderungen im EEG sowie der neuroradiologischen Bildgebung. In der Hirn-SPECT-Untersuchung fanden sich für eine DAT untypische ausgedehnte, vorwiegend rechtshemisphärische Perfusionsstörungen. Im weiteren Verlauf rasche Progredienz des Krankheitsbildes mit Entwicklung eines akinetischen Mutismus sowie Nachweis erhöhter Werte der neuronspezifischen Enolase und des 14-3-3-Proteins im Liquor. Der Patient verstarb schließlich unter dem Bild einer Decortication. Aufgrund des klinischen Verlaufs sowie der Liquorbefunde wurde, da eine autoptische Befundsicherung nicht vorliegt, die Diagnose einer wahrscheinlichen Creutzfeldt-Jakob-Erkrankung gestellt. Die vorgestellte Kasuistik unterstreicht aus unserer Sicht den Wert der Hirn-SPECT in der differentialdiagnostischen Abgrenzung dementieller Zustandsbilder.

Objectives - Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Creutzfeldt-Jakob disease (CJD) we examined the concentrations of malondialdehyde (MDA) as an established marker of lipid peroxidation. Material and methods -MDA was quantified by high performance liquid chromatography (HPLC) in cerebrospinal fluid (CSF; n=12) and in serum (n = 11) samples of CJD patients and healthy controls (n= 15). Results - Mean values in healthy controls: 2.56 nmol/ml±0.46 (CSF) and 1.94 nmol/ ml±0.67 (serum); mean values in CJD patients: 2.64 nmol/ml±0.67 (CSF) and 1.68 nmol/ml±0.79 (serum). No significant (P>0.05) difference between CJD patients and controls was observed. Conclusions - The results indicated that the CSF and serum of CJD patients showed no higher endogenous levels of MDA as compared to normal healthy controls. These findings provide no evidence for an additional role of oxidative stress in the pathogenetic mechanism underlying CJD neurodegeneration.

Zusammenfassung. Die Symptomatik «Demenz» kann durch eine Vielzahl zugrunde liegender Erkrankungen begrundet sein. Dabei ist es von besonderer Bedeutung, potenziell reversible Erkrankungen zu erkennen. In dieser Arbeit werden Patienten mit einer rasch pro- gredienten Demenz analysiert, die dem Nationalen Referenzzentrum fur Spongiforme Enzephalopathien in Gottingen gemeldet worden sind. Ein hoher Anteil von 35 % litt an potenziell reversiblen Erkrankungen, insbesondere entzundlichen und autoimmunen Erkrankungen. Unter den nicht-reversiblen Erkrankungen stand der M. Alzheimer erwartungsgemas im Vordergrund. Potenziell reversible Erkrankungen wiesen ein jungeres Alter bei Erkrankungsbeginn und eine tendenziell kurzere Krankheitsdauer auf. Unter den neurodegenerativen Er- krankungen waren die Patienten vorwiegend homozygot fur Methionin in Bezug auf den Polymorphismus am Codon 129 des Prionprotein Gens (PRNP). Dieser Befund ist in der Literatur als Risikofaktor fur die Creutzfeldt-Jakob-Erkrankung und den M. Alzheimer beschrie- ben. Die Studie umfasste ebenfalls ein Analyse der gangigsten neurodegenerativen Marker Gesamttau, β-Amyloid1-42, neuronenspezi- fische Enolase (NSE) und S100B. Dabei zeigten sich Unterschiede zwischen den Krankheitsgruppen fur Tau und S100B, wahrend β-Amyloid1-42 bei allen erniedrigt und NSE bei allen Patienten im Normbereich war. Daneben wurde ein innovativer Marker zur Verbesserung der Liquordiagnostik untersucht. Erniedrigte Transthyretin-Werte halfen bei der Differenzierung zwischen M. Alzheimer und gesunden Kontrollen, aber auch in Abgrenzung zu anderen neurodegenerativen Erkrankungen. Zusammenfassend kann die Darstel- lung klinischer Daten und etablierter und innovativer Liquormarker die Differenzialdiagnostik von Demenzen verbessern. Daneben werden seltene behandelbare Demenzursachen, die Hashimoto-Encephalopathie und die progressive Encephalopathie mit Rigor und Myoklonien (PERM), sowie ein Vorschlag zur Differenzialdiagnostik rasch progredienter Demenzen dargestellt. Abstract. The clinical sign «dementia» can be caused by a number of varying diseases. The recognition of potentially reversible diseases is of special importance in differential diagnosis. Here we present an analysis of patients with rapidly progressive dementia who were referred to the National Reference Centre for Spongiform Encephalopathy in Gottingen/Germany. A high proportion of 35 % had a potentially reversible dementia with mainly inflammatory and autoimmune disorders. Within the nonreversible disorders Alzheimer's disease was in the lead as expected. Patients with a potentially reversible dementia were younger at age at onset and showed shorter disease duration. PRNP cod on 129 genotype distribution showed a higher proportion of methionine homozygous patients in the group of non-reversible disorders.This has been described as risk factor for Creutzfeldt-Jakob disease and Alzheimer's disease before. This study also includes analysis of the established biomarkers such as total tau, β-Amyloid1-42, neuron specific enolase (NSE) and S100B. Differences were found for total tau and S100B while β-Amyloid1-42 was decreased in all diagnostic groups and NSE in normal range. As a potentially new diagnostic marker we investigated transthyretin concentrations in the CSF. Levels were markedly decreased for Alzheimer's disease in contrast to healthy controls and other neurodegenerative disorders. This data on clinical features and established and new CSF markers can improve differential diagnosis of rapidly progressive dementia. Additionally, two rare reversible disorders are presented in detail (Hashimoto encephalopathy and progressive encephalopathy with rigidity and myoclonus PERM) and an approach for differential diagnosis is given.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human transmissible spongiform encephalopathies (prion disease), but its cause has not been fully elucidated. According to its biochemical properties prion protein is resistant to routine sterilisation methods. Thus, invasive medical procedures could be involved in the genesis of the disease. Present knowledge about iatrogenic routes of transmission, oral infection and transmission via blood products in variant CJD (vCJD) underlines the importance of careful surveillance and analysis of potential routes of transmission. Several studies of risk factors for sCJD published in the past have given contrary results, which may be largely explained by different control groups. This article reviews epidemiology and classification of CJD and discusses possible risk factors and summarizes previous case-control studies.

Fatal familial insomnia (FFI)--first reported in 1986--is a hereditary prion disease with autosomal-dominant inheritance, caused by a missense-mutation at codon 178 of the prion-protein gene (PRNP) on chromosome 20. A methionine-valine polymorphism at codon 129 of PRNP expresses different phenotypes. The clinical features of FFI are characterized by a disrupted sleep-wake cycle with resulting fluctuations of vigilance, autonomic hyperactivation, myoclonus, motor abnormalities and by cognitive disturbances. The age of onset is between middle to late adulthood (51 +/- 7.1 years), disease duration varies between 8 and 72 months (18.4 +/- 17.3 months) and is ultimately fatal. We report the case of a 57-year-old man with a diagnosed FFI by molecular-genetic investigation who suffered from increasing memory- and sleep-disturbance as well as physical restlessness and impotence for 9 months. Clinical features were motor symptoms, generalized myoclonus and hyperactivity with reduced attention and concentration. The neuropsychological findings were a severe disturbance of attention and memory as well as incipient deficits in executive functions. The cranial MRI and repeated EEG were normal; in detailed laboratory tests including CSF no abnormalities were detected. The clinical course was characterized by rapid decline of the motor and cognitive skills; the patient died 15 months after onset. Histological analysis showed the typical changes of FFI (spongiform changes at hippocampus and regio entorhinalis, severe gliosis in the thalamus and mild deposits of abnormal prion protein).

BACKGROUND AND PURPOSE: Hyperintense basal ganglia on MR imaging support the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). Our aim was to study the frequency of patients with sporadic CJD presenting with and without characteristic basal ganglia lesions on MR imaging and to examine the corresponding patient characteristics. MATERIALS AND METHODS: Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted images (DWI) of 55 patients with CJD were assessed for signal-intensity increase (FLAIR) or restricted diffusion (DWI) in 7 cortex regions and the basal ganglia, thalamus, and cerebellum. Patient characteristics as well as electroencephalography, CSF, and codon 129 genotype of the prion protein gene (PRNP) were correlated with the most frequent MR imaging lesion patterns. RESULTS: Two major lesion patterns were identified by DWI: cortex and basal ganglia involvement (two thirds) and isolated cortex involvement (one third). In the latter patient group, the cortex involvement was widespread (at least 3 regions affected in 89% on DWI) and usually included the frontal and parietal lobes (78%). The length of the disease course was significantly prolonged (median, 12 versus 5 months). No significant differences were observed concerning electroencephalography and CSF findings and codon 129 genotype distributions. Of 4 patients with normal MR imaging findings, the CSF was positive for the 14-3-3 protein in 3. CONCLUSION: A high number of patients with CJD present without basal ganglia lesions on MR imaging. Isolated cortex involvement on DWI and FLAIR should lead to suggestion of CJD, even if the disease course is only slowly progressive. Additional 14-3-3 protein analysis in the CSF may support the CJD diagnosis.

In this article, authors analyzed a modern approach to the diagnosis of Creutzfeldt-Jakob disease (CJD) based on the clinical signs, cerebrospinal fluid markers, electroencephalography and magnetic resonance imaging. It was demonstrated for the first time that patients with late-onset CJD differed from younger CJD patients with respect to MRI profiles and initial clinical presentation. To date, cerebrospinal fluid (CSF) analysis, particularly protein 14-3-3 testing, presents an important approach to the identification of disease cases. A spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions. Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein. Recent studies applied the RT-QuIC methodology to CSF for the diagnosis of human prion diseases.В статье представлен анализ современных подходов к диагностике болезни Крейтцфельдта-Якоба (БКЯ), основанных на клинических признаках, маркерах цереброспинальной жидкости (ЦСЖ), электроэнцефалографии (ЭЭГ) и магнитно-резонансной томографии (МРТ). Установлено, что пациенты с поздним началом БКЯ отличаются от более молодых по данным МРТ и клинической картине в начале заболевания. На сегодняшний день важное значение в диагностике БКЯ придается исследованию ЦСЖ на белок 14-3-3. Спектр дифференциальной диагностики быстро прогрессирующей деменции широк и включает в себя как нейродегенеративные заболевания, так и деменции вследствие острых неврологических заболеваний. В последние годы для диагностики прионных заболеваний человека используется методика RT-QuIC при анализе ЦСЖ, которая основана на амплификации прионного белка, первоначально отработанной на определении прионного белка скрепи.

BACKGROUND AND PURPOSE: MR imaging has played an increasingly important role in the diagnosis of Creutzfeldt-Jakob disease (CJD) since basal ganglia abnormalities on T2-weighted images have been described; thus, the aim of our study was to compare the value of different MR images in the diagnosis of CJD. METHODS: One hundred fifty-seven patients with CJD underwent MR imaging examinations. Ninety-two patients were neuropathologically confirmed, and 65 were clinically classified as having CJD through the CJD Surveillance Unit (probability of 95%). There was no standardized MR imaging protocol; thus, the examinations included 143 T2-weighted, 43 proton attenuation (PD)-weighted, 84 fluid-attenuated inversion recovery (FLAIR), and 44 diffusion-weighted images (DWI). The MR images were reviewed for pathologic changes of the basal ganglia, thalamus, and cerebral cortex. 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 on FLAIR or T2-weighted images. CONCLUSION: PD-weighted images and DWI showed better results in the diagnosis of signal intensity changes in the basal ganglia compared with T2-weighted or FLAIR images; however, in the diagnosis of cortical changes, DWI was clearly superior. Our data suggest that DWI is the most sensitive MR imaging technique in the diagnosis of CJD.

Das Spektrum dementieller Erkrankungen, die als Differentialdiagnosen einer Creutzfeldt-Jakob-Krankheit (CJK) infrage kommen, ist unzureichend untersucht, jedoch fur die klinische Abgrenzung rasch fortschreitender Demenzen besonders wichtig. Seit dem Jahr 1993 werden in der Gottinger Arbeitsgruppe zur Epidemiologie und Fruherkennung humaner spongiformer Enzephalopathien die in Deutschland gemeldeten Verdachtsfalle einer CJK untersucht. In dieser Studie werden die haufigsten Differenzialdiagnosen der CJK und deren klinische Besonderheiten aufgezeigt, um die differenzierte Diagnosestellung zu prazisieren. In dem Zeitraum von Juni 1996 bis Mai 1999 wurden 541 Patienten mit dem Verdacht auf eine CJK gemeldet und von einem Neurologen der Arbeitsgruppe untersucht. 157 Patienten erfullten nicht die Klassifikationskriterien der CJK (nach der WHO 1998; BIOMED 2-Studie 1998 – Zerr, Neurology 2000) fur eine „mogliche“ oder „wahrscheinliche“ CJK und wurden daher als „andere Erkrankung“ klassifiziert. Anhand katamnestischer Erhebungen konnte das Spektrum der Differenzialdiagnosen erstellt werden. Die endgultige Diagnose wurde aufgrund des neuropathologischen Befundes oder unter der Anwendung von etablierten klinischen Klassifikationskriterien gestellt. Bei 30 Patienten konnte ein Morbus Alzheimer (13 neuropathologisch bestatigt) und bei 16 Patienten eine vaskulare Demenz diagnostiziert werden. In 11 Fallen war die Symptomatik durch einen entzundlichen Prozess des zentralen Nervensystems (ZNS) und bei 7 Patienten durch eine Enzephalopathie (metabolisch, toxisch, paraneoplastisch) verursacht. Die Kriterien fur eine Lewy-Korperchen-Erkrankung erfullten 7 Patienten, 3 hatten eine frontotemporale Demenz, 3 eine Multisystematrophie, 2 Patienten eine kortikobasale Degeneration, 2 eine Chorea Huntington und ein Patient war an einer Hashimoto-Enzephalitis erkrankt. Bei weiteren einzelnen Differenzialdiagnosen handelte es sich vorwiegend um psychiatrische Erkrankungen. Inwieweit sich die einzelnen Erkrankungen voneinander differenzieren lassen wird anhand der klinischen Symptomatik, dem Liquor (Proteine 14–3-3, NSE, Protein S 100), EEG und MRT dargestellt. Bei keinem Patienten stellte sich eine CJK heraus, so dass sich die Klassifikationskriterien als sehr genau bewiesen. Die haufigsten Differenzialdiagnosen der CJK waren ein schnell fortschreitender Morbus Alzheimer gefolgt von den vaskularen Demenzen und den entzundlichen Erkrankungen des ZNS.

Ziele: Die Diagnose der CJD wird an autoptisch oder bioptisch gewonnenem Hirngewebe gestellt. Die Magnetresonanztomographie spielt eine zunehmend wichtige Rolle, seit Stammganglienanomalien in T2w- und PDw- Sequenzen beschrieben wurden. Einzelberichte von der Nutzlichkeit von FLAIR oder diffusionsgewichteter MRT (DWI) wurden kurzlich veroffentlicht. Das Ziel unserer Studie war die Bestimmung der Wertigkeit verschiedener MR-tomographischer Verfahren (T2w, PDw, FLAIR, DWI) in der Diagnostik der CJD. Methode: 154 Patienten mit klinisch „wahrscheinlicher“ CJD (p>95%) wurden MR-tomographisch untersucht und retrospektiv ausgewertet. Es lagen vor: 141 T2w-, 43 PDw-, 84 FLAIR- und 44 DWI-Untersuchungen. Die Untersuchungen wurden bzgl. pathologischer Veranderungen in den Basalganglien (getrennt in Putamen und Nucl. caudatus), des Thalamus und des Cortex cerebri ausgewertet. Ergebnis: Hyperintense Signalveranderungen wurden im Putamen mit den verschiedenen MR-Techniken in folgenden Haufigkeiten gefunden: T2w 38% (54/141), PDw 58% (25/43), FLAIR 37% (31/84) und DWI 45% (20/44). Die korrespondierenden Werte fur den Nucl. caudatus waren: T2w 35% (50/141), PDw 63% (27/43), FLAIR 48% (40/84) und DWI 64% (28/44). Im Thalamus fanden sich folgende Werte: T2w 5% (7/141), PDw 19% (8/43), FLAIR 8% (7/84), DWI 14% (6/44). Im Nachweis hyperintenser Signalveranderungen im Cortex cerebri zeigten sich jedoch deutliche Unterschiede in der Empfindlichkeit der verschiedenen MR-Techniken: T2w 6% (8/141), PDw 19% (8/43), FLAIR 50% (42/84), DWI 77% (34/44). Schlussfolgerung: Bezuglich des Nachweises hyperintenser Signalveranderungen in den Stammganglien und des Thalamus wiesen die verschiedenen MR-Untersuchungstechniken keine signifikanten Unterschiede auf. FLAIR und DWI waren den anderen MR-Untersuchungstechniken im Nachweis hyperintenser Kortexveranderungen deutlich uberlegen. DWI war die sensitivste Untersuchungstechnik zum Nachweis der bisher selten beschriebenen hyperintensen kortikalen Signalveranderungen bei CJD.

Analogous to prospective studies in other countries, prevalance and symptoms of sporadic Creutzfeldt-Jakob disease (CJD) were recorded in order to assess irregularities in the incidence of the disease in Germany since the onset of bovine spongioform encephalopathy (BSE).SInce 1993 all suspected case of CJD reported in the Federal Republic of Germany have been analysed by a unified schema and classified by standardised criteria. In addition to voluntary reporting two other systems were accessed: (1) compulsory reporting to the Robert Koch Institute via the appropriate Health Department and (2) cause of death statistics of the Federal Office of Statistics.Between June 1993 and May 2001, a total of 1247 patients with suspected CJD, obtained by the angle quotation mark, rightStudy of the epidemiology and early diagnosis of human spongioform encephalopathiesangle quotation mark, left at Göttingen University, were examined. The suspected disease was confirmed by autopsy in 404 cases, the diagnosis of probable CJD was made in 369 cases on the basis of clinical data and additional investigation. At the beginning of the Göttingen Study in 1993 the incidence in Germany was 0.7 per mill. population, while in the year 2000 it had risen to 1.3 per mill. population. Corresponding increases in the number of cases since 1993 have been noted also by the Robert Koch Institute and the Federal Office of Statistics.The increased incidence can be explained primarily by a decrease in previously unknown cases. Concerted action as part of the Göttingen Study has increased the cooperation of associated clinics. In addition to sporadic cases of CJD, genetic and, more rarely, iatrogenic forms have been seen in Germany. But no cases of new variant CJD have been reported so far.

Background: The cause of sporadic Creutzfeldt–Jakob disease (CJD) is unknown. Previous studies found a link with a history of surgery but had methodologic problems. Objective: To help elucidate medical and associated risk factors for sporadic CJD as part of the 1993 to 1995 European Union collaborative studies of CJD. Methods: Medical and associated risk factors from 326 patients with sporadic CJD, taken from population-based studies performed between 1993 and 1995 in France, Germany, the Netherlands, and the UK, were compared with 326 community controls recruited by telephone in 2000. Results: A history of surgery was significantly associated with the risk of sporadic CJD (odds ratio [OR]: 1.8; 95% CI: 1.2 to 2.6), which was not dependent on the number of surgical procedures, and was stronger in females (OR: 2.5; 95% CI: 1.5 to 4.0). Gynecologic (OR: 1.5; 95% CI: 1.0 to 2.3) and “other” operations (any operation other than neurologic, eye, ear, gallbladder, gastrointestinal, and gynecologic operations, tonsillectomy, and appendectomy) (OR: 1.5; 95% CI: 1.1 to 2.1) were associated with risk of CJD. Tonsillectomy (OR: 0.3; 95% CI: 0.2 to 0.5) and appendectomy (OR: 0.6; 95% CI: 0.4 to 0.8) were observed less frequently in cases. An increased risk was also found with a history of ear piercing in females (OR: 1.6; 95% CI: 1.1 to 2.5) and psychiatric visit(s) (OR: 2.6; 95% CI: 1.5 to 4.3). Conclusions: These results support the hypothesis that cases of sporadic CJD may result from hitherto unrecognized surgical contamination events. However, because of the limits of the study design, the rarity of the disease, and the potential for bias, the results should be interpreted with caution.

Until recently, the clinical diagnosis of CJD relied mainly on three criteria. These include patient history (rapidly progressive dementia), neurological findings (ataxia, pyramidal/extrapyramidal signs, myoclonus, akinetic mutism) and typical electroencephalographic (EEG) findings. These criteria are fulfilled in typical cases. The occurrence or increase of certain proteins in cerebrospinal fluid (CSF; 14-3-3, neuron-specific enolase) now provide important adjuncts in recognizing variant forms. Although these proteins can be detected in other neurological diseases accompanied with substantial brain damage such as encephalitis, they are also characterized by their high sensitivity and specificity with regard to other dementing processes (Alzheimer and vascular dementia). The increase in the number of positive cases during the last years in Germany reflects an improved case ascertainment rather than the appearance of the variant CJD (vCJD). Although several recent cases with a long duration of the disease were actually recognized, they did not reveal the typical florid plaques at autopsy. They were revealed as a rare variant of sporadic CJD, which is characterized by homocygosity for valine at codon 129 and PrP(Sc) type 1. This variant is positive for the 14-3-3 protein in CSF. Further subtypes described by Parchi et al. can also be characterized by a certain pattern of clinical symptomatology, EEG- and 14-3-3-findings. In addition, differential diagnosis revealed some treatable dementias among the most common diseases (Alzheimer and vascular dementia) such as herpes encephalitis, multiple sclerosis and Hashimoto encephalitis, particularly in the younger age group.

Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Creutzfeldt-Jakob disease (CJD) we examined the concentrations of malondialdehyde (MDA) as an established marker of lipid peroxidation.MDA was quantified by high performance liquid chromatography (HPLC) in cerebrospinal fluid (CSF; n=12) and in serum (n=11) samples of CJD patients and healthy controls (n = 15).Mean values in healthy controls: 2.56 nmol/ml +/- 0.46 (CSF) and 1.94 nmol/ ml +/- 0.67 (serum); mean values in CJD patients: 2.64 nmol/ml +/- 0.67 (CSF) and 1.68 nmol/ml +/- 0.79 (serum). No significant (P0.05) difference between CJD patients and controls was observed.The results indicated that the CSF and serum of CJD patients showed no higher endogenous levels of MDA as compared to normal healthy controls. These findings provide no evidence for an additional role of oxidative stress in the pathogenetic mechanism underlying CJD neurodegeneration.

To assess the attitude of Creutzfeldt-Jakob patients relatives and of relatives of cognitively unimpaired individuals towards dementia research by a questionnaire survey.42 relatives of cases and 41 controls who were interviewed within the german part of the European Union collaborative study of CJD were asked to answer structured questions concerning their personal attitude towards three hypothetical projects: a diagnostic research project without personal benefit, a project with possible therapeutic option and a study of hereditary dementia.31 relatives of cases and 26 relatives of the controls were willing to participate in this survey. In both groups the willingness to participate in dementia research is high. Research without approval of patients or relatives is rejected in most cases. Relatives want to decide to which extent genetic results are used for scientific or personal purposes.Although research with (and for) demented patients is restricted by the law in many countries to certain limits, relatives are willing to participate in these efforts to a greater extend than expected. As long as the responsible physicians will respect their demented patients as severely ill human beings, the view towards research is this field might be as positive as shown in this sample.