Andreas Schröter

Current clinical diagnosis in Creutzfeldt‐Jakob disease: Identification of uncommon variants

According to the recently established molecular basis for phenotypic heterogeneity of sporadic Creutzfeldt‐Jakob disease (CJD), six different phenotypes are characterized by the size of the protease‐resistant fragment of the pathological prion protein (types 1 and 2) and homozygosity or heterozygosity for methionine or valine at codon 129 of the prion protein gene (designated by MM1, MM2, MV1, MV2, VV1, and VV2). In the present investigation, we analyzed the value of commonly used clinical tests (electroencephalogram [EEG], detection of 14‐3‐3 protein in cerebrospinal fluid [CSF], and hyperintensity of the basal ganglia in magnetic resonance imaging) for the clinical diagnosis in each CJD phenotype. The detection of periodic sharp and slow wave complexes in the EEG is reliable in the clinical diagnosis of MM1 and MV1 patients only. The CSF analysis for 14‐3‐3 protein showed high sensitivity in all analyzed subgroups with the exception of MV2 patients. Valine‐homozygous patients had a negative EEG, but most had detectable levels of neuronal proteins in the CSF. The sensitivity of the magnetic resonance imaging was 70%, irrespective of the subgroup, but was particularly reliable in the clinical diagnosis of MV2 patients. The widening spectrum of diagnostic techniques in CJD is not only useful in the increased accuracy of the clinical diagnosis but should also lead to the identification of more atypical cases of sporadic CJD. Ann Neurol 2000;48:323–329

Positron emission tomography with [18F]FDG in the diagnosis of Creutzfeldt-Jakob disease (CJD)

Abstract. The aim of this study was to explore the sites of metabolic changes with [18F]2-fluoro-2-desoxy-D-glucose (FDG) and positron emission tomography (PET) in patients with Creutzfeldt-Jakob disease and to correlate the findings with clinical symptoms. Static [18F]FDG-PET studies of eight patients with the diagnosis of confirmed or probable CJD were retrospectively analysed by two physicians from departments of nuclear medicine independently with a strong interrater agreement (κ=0,98). The clinical data of the patients, based on a standardized evaluation by physicians from the German Creutzfeldt-Jakob disease surveillance study, was correlated with the PET findings. [18F]FDG-PET shows widespread hypometabolism in CJD. All patients had a reduction of cerebral glucose metabolism in at least one temporal or parietal region. Additionally in 7 of our own 8 cases and 3 of 4 cases from the literature the occipital lobe, the cerebellum or the basal ganglia were involved. These findings differ from typical patterns of hypometabolism in Alzheimers disease and other neurodegenerative disorders. In two thirds of the cases the distribution was markedly asymmetric. Myoclonus was present in five out of our eight own cases. Our data suggest that myoclonus might correlate with metabolic impairment of contralateral parietal and temporal lobes. In three of four patients with visual symptoms FDG uptake was reduced in the visual cortex bilaterally. Typical hyperintensities on MRI were only found in two of the eight cases at the time of PET-studies. Our results demonstrate that [18F]FDG-PET appears to be a sensitive investigation in CJD and could be useful to differentiate CJD from other neurodegenerative disorders.

Increased Lipid Peroxidation in Cerebrospinal Fluid and Plasma from Patients with Creutzfeldt-Jakob Disease

Oxidative pathomechanisms play an important role in neurodegenerative diseases like Alzheimers disease (AD). It has been shown that lipid peroxidation in cerebrospinal fluid (CSF) and plasma is increased in AD. To assess the role of oxidative stress in Creutzfeldt-Jakob disease (CJD), we investigated the oxidizability of lipids, the lipid composition and the levels of the antioxidants ascorbate and alpha-tocopherol in CSF and plasma of 15 CJD patients and 12 neurologically healthy controls. CSF and plasma lipid peroxidation was increased in CJD patients and polyunsaturated fatty acids were reduced in CSF of these patients. Ascorbate levels were lower in CSF and plasma of CJD patients, while alpha-tocopherol was found to be decreased in CSF but not in plasma. These results support the hypothesis that oxidative mechanisms are involved in the pathogenesis of CJD and provide a rationale for the use of antioxidants in the therapy of this disease.

Diffusionsgewichtetes MRT bei Creutzfeldt-Jakob-Patienten

ZusammenfassungDie sichere Diagnose der Creutzfeldt-Jakob-Krankheit kann nur bioptisch oder autoptisch durch Untersuchung von Hirngewebe gestellt werden. Die klinische Verdachtsdiagnose erhärten können technische und laborchemische Untersuchungen; hierzu gehört neben dem EEG die Surrogatmarkerbestimmung im Liquor. Nachdem sich bei der Mehrzahl der Patienten Veränderungen der Basalganglien gezeigt haben, gehört das MRT zu den bildgebenden Verfahren, die bei Verdacht auf CJD eingesetzt werden können. Inzwischen ist die Diffusionswichtung (DWI) in die neuroradiologische Diagnostik eingeführt worden.DWI-gewichtete MRTs bei 5 CJD-Patienten wurden von uns untersucht. Alle 5 Fälle zeigten im DWI-MRT signalintense Veränderungen der Stammganglien. Diese Veränderungen waren jeweils deutlicher als in der T2, Flair- oder Protonenwichtung. Das DWI-MRT halten wir für sensitiver zum Nachweis kortikaler und basaler Veränderungen bei CJD-Patienten im Vergleich zu Standardsequenzen. Durch die kurze Untersuchungszeit können besonders bei den häufig vorhandenen Myoklonien andere Wichtungen aufgrund von Bewegungsartefakten oftmals nicht in der gewünschten Qualität durchgeführt werden.SummaryToday the diagnosis of Creutzfeldt-Jakob disease (CJD) is proven only postmortem or by evidence of neuropathology. During the patients lifetime EEG recordings or cerebrospinal fluid analysis may support the diagnosis. In most cases, T2-MRI scans show hyperintensities of the basal ganglia. A new imaging technique called diffusion-weighted MRI (DWI) has recently been established. The sensitivity of DWI was evaluated in five patients suspected of CJD. All five cases showed hyperintense signal changes in the basal ganglia on DWI sequences. These findings were more pronounced in DWI than in T2, FLAIR, or PD-weighted images. Thus, DWI seems to be the most sensitive sequence for detecting changes in patients with suspected CJD. Moreover, its short scanning time ensures that fewer artifacts occur, especially in the case of myoclonus.

Evidence for a Pathogenic Role of Different Mutations at Codon 188 of PRNP

Clinical and pathological changes in familial Creutzfeldt-Jakob disease (CJD) cases may be similar or indistinguishable from sporadic CJD. Therefore determination of novel mutations in PRNP remains of major importance. We identified two different rare mutations in codon 188 of the prion protein gene (PRNP) in four patients suffering from a disease clinically very similar to the major subtype of sporadic CJD. Both mutations result in an exchange of the amino acid residue threonine for a highly basic residue, either arginine (T188R) or lysine (T188K). The T188R mutation was found in one patient and the T188K mutation in three patients. The prevalence of mutations at codon 188 of PRNP was tested in 593 sporadic CJD cases and 735 healthy individuals. Neither mutation was found. The data presented here argue in favor of T188K being a pathogenic mutation causing genetic CJD. Since one individual with this mutation, who is the father of a clinically affected patient with T188K mutation, is now 79 years old and shows no signs of disease, this mutation is likely associated with a penetrance under 100%. Further observations will have to show whether T188R is a pathogenic mutation.

The effect of stress on the onset and progression of Creutzfeldt-Jakob disease: results of a German pilot case-control study.

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 one of the following three subgroups: psychosocial stress events, medical operations with hospitalisation, and other serious medical examinations. A significantly higher proportion of CJD cases experienced stressful life events during the last six months before disease onset than controls (65% vs. 32%, p = 0.01), yielding an odds ratio (OR) of 3.85 (95% confidence interval (CI): 1.33–11.30). We found the clearest distinction between cases and controls for the subgroup of medical operations where an OR of 6.97 (95% CI: 0.76–329.20) was observed. Further data indicated that stressful events seem to influence not only the onset of CJD but also the progression of the disease. Although based on a rather small study sample, this pilot case–control investigation suggests evidence that stressful life events in the last six months before disease onset may influence CJD occurrence and may modify the course of disease. This ‘stress hypothesis’, which is in line with findings from other epidemiological and experimental studies in CJD, is thus a promising direction for future CJD research as it could enlighten the pathophysiological mechanisms and point towards strategies for the prevention and therapy of CJD.

Different binding pattern of antibodies to prion protein on lymphocytes from patients with sporadic Creutzfeldt-Jakob disease.

In Creutzfeldt-Jakob disease (CJD), progressive neuronal cell death probably occurs as a result of a change in conformation of the physiological prion protein (PrP(C)). There is evidence of participation of the lymphatic system and in particular of lymphocytes in the intracorporeal transportation of the pathological prion protein (PrP(Sc)) in new variant CJD and scrapie. Using fluorescence cytometry, we investigated a possible alteration of PrP(C) on lymphocytes of patients with sporadic CJD. We demonstrated a significantly lower binding pattern of antibodies (3F4) against physiological prion protein to lymphocytes of patients with sporadic CJD (n=16) compared with control patients. In contrast this difference was not found on platelets (n=23). For the first time we were able to present a measurable difference of antibody binding on lymphocytes of patients with CJD. One interpretation of this finding is that lymphocytes patrolling the brain bind and transport PrP(Sc) which has a lower binding affinity for the antibodies directed against physiological PrP.

Unaltered apoptotic behaviour of mononuclear cells from patients with sporadic Creutzfeldt-Jakob disease

Abstract Creutzfeldt-Jakob disease (CJD) belongs to the group of transmissible spongiform encephalopathies. It is suspected that a pathologically altered form of the prion protein (PrPSc) is the decisive trigger of the disease. Data from animal experiments suggest an involvement of the lymphatic system in the intracorporal transport of PrPSc. However, it has not so far been possible to detect PrPSc on mononuclear cells (MNCs) either in the sporadic form of CJD or in the new variant of CJD (vCJD). In order to determine a possible alteration of MNCs in CJD, we investigated the natural and induced apoptotic behaviour of these cells.MNCs from 19 patients with sporadic CJD and from 20 patients with other neurological disorders were used. The cells were analysed by fluorescence cytometry with and without apoptosis induction by xanthine oxidase and hypoxanthine. The apoptosis rate was quantified using the stain 7-amino-actinomycin D (7-AAD). In the morphological investigation of the cells before apoptosis induction, there were no significant differences between the groups with regard to cell size and granularity of the MNCs. After apoptosis induction, the typical significant decrease in cell size and increase in granularity of the cells occurred in both groups. Significant differences between the patient populations were not found.For the first time, our investigation has demonstrated that a functional impairment of MNCs with regard to their apoptotic behaviour does not occur in sporadic CJD. It remains open to question whether this mechanism plays an important role in forms of transmissible encephalopathy other than sporadic CJD, especially after oral transmission.