Latrogenic Creutzfeldt-Jakob disease with florid plaques.

Florid plaques indistinguishable from those found in vCJD were identified at a postmortem examination in the brain of a 58-year-old clinical suspect case of Creutzfeldt-Jakob disease (CJD). Western blotting of brain tissue revealed an unusual prion protein type. Since the patient had received a dura mater graft 20 years prior to death and florid plaques are not only found in new variant CJD, the findings argue in favor of an iatrogenic origin of the disease with the longest incubation time following a dura mater graft reported to date even though he may have been exposed to BSE. The peculiar pathological, clinical and biochemical features may define a new type of human prion disease.

Clinical diagnosis and differential diagnosis of CJD and vCJD. With special emphasis on laboratory tests.

The most widely distributed form of transmissible spongiform encephalopathy, sporadic Creutzfeldt-Jakob disease, typically affects patients in their sixties. Rapidly progressive dementia is usually followed by focal neurological signs and typically myoclonus. The disease duration in sporadic CJD is shorter than in variant CJD (6 months and 14 months, respectively). The clinical diagnosis in sporadic CJD is supported by the detection of periodic sharp and slow wave complexes in the electroencephalogram, hyperintense signals in basal ganglia on magnetic resonance imaging and elevated levels of neuronal proteins in the cerebrospinal fluid (such as 14-3-3). In contrast to the sporadic form, hyperintense signals in the posterior thalamus ("pulvinar sign") are seen in variant CJD. Following recent developments in diagnostic premortem techniques, clinical criteria for probable sporadic and probable variant CJD were established. Clinicopathological studies on sporadic CJD revealed different phenotypes which are characterized by neuropathological lesion profile, clinical syndrome, codon 129 genotype and type of proteinase K-resistant core of the prion protein. Alzheimer's disease and Lewy body dementia are the most frequent differential diagnoses in sporadic CJD in elderly patients, whereas chronic inflammatory disorders of the central nervous system have to be considered in younger patients.

Autoantibody synthesis in primary progressive multiple sclerosis patients treated with interferon beta-1b.

We conducted an open-labeled clinical trial of interferon beta-1b (IFNB) treatment in 20 patients with primary progressive multiple sclerosis (PPMS) and longitudinally monitored autoantibodies against double-stranded DNA (dsDNA), thyroid peroxidase (TPO),myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin and S-100B. Before treatment, one patient had elevated TPO antibodies, four patients had elevated antibodies against S-100B, two patients against MOG or synapsin and one patient against MBP. In two patients we observed a continuous increase of dsDNA or TPO antibodies above the normal range. This rise paralleled IFNB treatment. In addition, 11 of 20 patients developed neutralizing antibodies against IFNB. There was no increase of autoantibodies directed against central nervous system antigens. Like patients with relapsing remitting or secondary progressive multiple sclerosis, PPMS patients may be at risk of an autoimmune response during IFNB treatment.

Interferon-beta-1 b decreased matrix metalloproteinase-9 serum levels in primary progressive multiple sclerosis.

Recent reports have shown that matrix-metalloproteinases (MMPs) facilitate T-cell migration into the CNS and play a role in disruption of the blood-brain-barrier and myelin break-down. An increase of MMP-9 serum levels predicts disease activity in relapsing remitting multiple sclerosis (RRMS). Interferon-beta (IFN-beta), which is an established treatment for RRMS, inhibits T-cell migration in vitro in parallel with the downregulation of MMP expression. Only limited data are available for primary progressive multiple sclerosis (PPMS) which differs in demographic and immunological aspects as well as in MRI criteria from RRMS. In this study, 19 patients with laboratory-supported definite PPMS were treated with 8 x 10(6) IU IFN-beta1b (Betaferon) subcutaneously every other day. Serum was collected before treatment and on months 1, 2, 3, 6 and 9 during treatment. Levels of MMP-9 and of its natural inhibitor known as tissue-inhibitor of matrix-metalloproteinase-1 (TIMP-1) were quantified by ELISA. In addition MMP-2 serum levels were determined by zymography. 19 healthy volunteers served as controls. Before treatment serum levels of MMP-9 were elevated in patients with PPMS compared with controls, whereas there was no difference in TIMP-1 serum levels. During treatment with IFN- beta1b the concentration of MMP-9 in the serum of 18 out of 19 PPMS patients decreased,whereas serum levels of MMP-2 and TIMP-1 remained nearly unaffected. Our results demonstrate that the MMP-9 to TIMP-1 ratio in patients with PPMS is elevated in comparison with healthy controls. The suppression of MMP-9 by IFN-beta1b indicates that this drug is immunomodulatory active in PPMS patients. Further studies are necessary to test if IFN-beta exerts a beneficial effect in PPMS.

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

The aim of this study was to explore the sites of metabolic changes with [(18)F]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 [(18)F]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 (kappa=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. [(18)F]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 Alzheimer's 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 [(18)F]FDG-PET appears to be a sensitive investigation in CJD and could be useful to differentiate CJD from other neurodegenerative disorders.

Interferon-beta-1b increases serum interleukin-12 p40 levels in primary progressive multiple sclerosis patients.

Serum levels of interleukin-12 heterodimer (IL-12p70) and its homodimeric subunit (IL-12p40) were analyzed by enzyme-linked immunosorbent assay in 18 patients with primary progressive multiple sclerosis (MS) during 3 months before and 3 months under treatment with interferon-beta-1b (IFNbeta-1b, Betaferon(), eight million units (MIU) every other day subcutaneously). Median IL-12p40 levels in MS patients before treatment (66.5 and 63.9 pg/ml) were not elevated compared to 18 healthy controls. IL-12p40 significantly increased during treatment (P<0.0001, median 105.3 pg/ml after 1 month and 95.3 pg/ml after 3 months). Detectable serum levels of IL-12p70 before therapy were only found in one patient. IL-12p70 did not increase during treatment. These data show that immunological processes may also play a role in primary progressive MS and that IFNbeta-1b has an immunomodulating effect in this particular MS subtype.

Heart fatty acid binding protein as a potential diagnostic marker for neurodegenerative diseases.

The diagnosis of neurodegenerative diseases with dementias requires several different test approaches and often remains uncertain. Using a proteomic approach it was shown in nine patients that heart fatty acid binding protein (H-FABP) might be a biomarker for Creutzfeldt-Jakob disease (CJD). The aim of our study was to evaluate whether H-FABP is a biomarker for the differential diagnosis of dementias. Therefore we measured H-FABP in cerebrospinal fluid (CSF) and serum of patients having CJD, dementia with Lewy-bodies (DLB), Alzheimer's disease (AD) and in non-demented control (NDC) patients. H-FABP levels in CSF and serum of CJD patients are increased compared to non-demented controls. Levels of H-FABP were significantly higher in CJD patients compared to AD and DLB in CSF. However, discrimination between CJD and AD was not possible in serum. Interestingly, highest levels of H-FABP were found in serum of DLB patients. Our results suggest that H-FABP might be a useful biomarker for the differentiation between the dementias examined if levels in CSF and serum are determined in parallel.

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.

[Course of anxiety, depression, and quality of life in relatives of patients with Creutzfeldt-Jakob-Disease] / Verlauf von Angst, Depressivität und Lebensqualität bei Angehörigen von Creutzfeldt-Jakob-Kranken (CJK).

Creutzfeldt-Jakob-Disease (CJD) is a rapidly progressing fatal disease. Most patients will not know the diagnosis, they leave reality in an early stage and go into dementia. The most afflicted persons are their relatives. They are forced to observe the patients' physical and mental decline. In this survey we included all cases of CJD who were registered in Germany within seven months. Questionnaires were sent to the closest relatives (n = 58). The response rate (n = 42) was acceptable. There was a high prevalence of abnormal anxiety and depression scores and bad quality of life. One fourth (n = 10) took part in a self-help meeting in Göttingen. Six months later, a follow-up assessment showed that relatives, who had participated in the self-help meeting, had significantly (p < 0,05) improved quality of life although their high levels of anxiety and depression persisted. The non-participants had no changes of depression or quality of life, but slightly improved anxiety. The severe psychological burden of these relatives could be a reaction to the physical and mental fall of the CJD-patient. It is higher that that of relatives of patients with different diseases in the literature. Special support for this group of relatives seems necessary.

Serum heart-type fatty acid-binding protein and cerebrospinal fluid tau: marker candidates for dementia with Lewy bodies.

BACKGROUND: The measurement of biomarkers in cerebrospinal fluid (CSF) has gained increasing acceptance in establishing the diagnosis of some neurodegenerative diseases. Heart-type fatty acid-binding protein (H-FABP) was recently discovered in CSF and serum of patients with neurodegenerative diseases. OBJECTIVE: We investigated H-FABP in CSF and serum alone and in combination with CSF tau protein to evaluate these as potential biomarkers for the differentiation between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: We established H-FABP and tau protein values in a set of 144 persons with DLB (n = 33), Parkinson disease with dementia (PDD; n = 25), AD (n = 35) and nondemented neurological controls (NNC; n = 51). Additionally, serum H-FABP levels were analyzed in idiopathic Parkinson disease patients without evidence of cognitive decline (n = 45) using commercially available enzyme-linked immunosorbent assays. We calculated absolute values of H-FABP and tau protein in CSF and serum and established relative ratios between the two to obtain the best possible match for the clinical working diagnosis. RESULTS: Serum H-FABP levels were elevated in DLB and PDD patients compared with NNC and AD subjects. To better discriminate between DLB and AD, we calculated the ratio of serum H-FABP to CSF tau protein levels. At the arbitrary chosen cutoff ratio > or =8 this quotient reached a sensitivity of 91% and a specificity of 66%. CONCLUSION: Our results suggest that the measurement of CSF tau protein, together with H-FABP quantification in serum and CSF, and the ratio of serum H-FABP to CSF tau protein represent marker candidates for the differentiation between AD and DLB.

Beta-amlyoid 1-42 and tau-protein in cerebrospinal fluid of patients with Parkinson's disease dementia.

Measurement of tau-protein and beta-amyloid(1-42 )(Abeta42) in cerebrospinal fluid (CSF) has gained increasing acceptance in the differential diagnosis of Alzheimer's disease. We investigated CSF tau-protein and Abeta42 concentrations in 73 patients with advanced idiopathic Parkinson's disease with dementia (PDD) and 23 patients with idiopathic Parkinson's disease without dementia (PD) and in a comparison group of 41 non-demented neurological patients (CG) using commercially available enzyme-linked-immunoabsorbant-assay (ELISA). tau-Protein levels were statistically significantly higher and Abeta42 lower in the PDD patients compared to PD patients and the CG. This observation was most marked (p < 0.05) in a subgroup of patients with PDD carrying the apolipoprotein genotype epsilon3/epsilon3. The distribution of the apolipoprotein genotypes in PDD and PD patients was similar to that of the CG. Although a significant difference in tau-protein values was observed between PDD and CG, no diagnostic cut-off value was established. These findings suggest that such protein CSF changes may help to support the clinical diagnosis of cognitive decline in PD and that there may be apolipoprotein-E-isoform-specific differences in CSF protein regulation in advanced PDD.

Follow-up investigations of tau protein and S-100B levels in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

BACKGROUND: S-100B and tau protein have a high differential diagnostic potential for the diagnosis of Creutzfeldt-Jakob disease (CJD). So far there has been only limited information available about the dynamics of these parameters in the cerebrospinal fluid (CSF). However, there is a special interest in finding biochemical markers to monitor disease progression for differential diagnosis and treatment. PATIENTS AND METHODS: We analyzed CSF of 45 patients with CJD and of 45 patients with other neurological diseases for tau protein and S-100B in a follow-up setting. All diagnoses of CJD were later neuropathologically verified. A ratio between tau protein differences and the time between lumbar puncture was calculated. The same was done for S-100B. RESULTS: Tau protein levels of 34 cases were above the cut-off level for CJD (>1,300 pg/ml) in the first CSF sample. In 7 of 11 patients with lower tau levels in the first CSF sample, tau levels rose. The above-mentioned ratio was significantly higher in the CJD group than in the group with other neurological diseases. Similar results were obtained for S-100B. CONCLUSION: We conclude that follow-up investigations and calculation of ratios is a useful tool in the differential diagnosis of CJD. Variations in this pattern were observed in single cases.

Tau protein, Abeta42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies.

The intra vitam diagnosis of dementia with Lewy bodies (DLB) is still based on clinical grounds. So far no technical investigations have been available to support this diagnosis. As for tau protein and beta-amyloid(1-42) (Abeta42), promising results for the diagnosis of Alzheimer's disease (AD) have been reported; we evaluated these markers and S-100B protein in cerebrospinal fluid (CSF), using a set of commercially available assays, of 71 patients with DLB, 67 patients with AD and 41 nondemented controls (NDC) for their differential diagnostic relevance. Patients with DLB showed significantly lower tau protein values compared to AD but with a high overlap of values. More prominent differences were observed in the comparison of DLB patients with all three clinical core features and AD patients. Abeta42 levels were decreased in the DLB and AD groups versus NDC, without significant subgroup differences. S-100B levels were not significantly different between the groups. Tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited especially due to mixed pathology. We conclude that more specific markers have to be established for the differentiation of these diseases.

Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease.

In 1996, our group published objective electroencephalogram (EEG) criteria to define periodic sharp-wave complexes (PSWCs) suggestive for Creutzfeldt-Jakob disease (CJD). These criteria have since then been strictly applied in all cases reported to us as possible CJD in the course of the German CJD surveillance study. Furthermore, EEG analysis of the records was performed without any additional information on complementary clinical and laboratory data. In this study, we investigated sensitivity, specificity, and the predictive values of these EEG criteria exclusively in cases in which autopsy confirmed (n=150) or excluded (n=56) CJD. EEG criteria were positive in 64% (n=96) of the CJD cases and falsely positive in 9% (n=5) of other dementias. The resulting figures for sensitivity, specificity, and positive and negative predictive values were 64%, 91%, 95%, and 49%, respectively. In the falsely positive cases, Alzheimer's disease (n=4) and vascular dementia (n=1) were the underlying diseases. However, only in one of these five cases both clinical and EEG data would have led to the false-positive result to diagnose probable CJD. These data prove the high diagnostic value of our objective EEG criteria in CJD.

Increased lipid peroxidation in cerebrospinal fluid and plasma from patients with Creutzfeldt-Jakob disease.

Oxidative pathomechanisms play an important role in neurodegenerative diseases like Alzheimer's 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.

Beta-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

Decreased levels of beta-amyloid peptide 1-42 (Abeta1-42) in cerebrospinal fluid (CSF) are a characteristic feature of Alzheimer's disease (AD) but recently were also observed in Creutzfeldt-Jakob disease (CJD). We analyzed the CSF of patients with CJD, and AD and nondemented controls using a quantitative urea-based Abeta sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot. Like in AD and nondemented controls, we found a highly conserved pattern of carboxyterminally truncated Abeta1-37/38/39 in addition to Abeta1-40/42 also in CJD patients. By the introduction of the ratio Abeta1-39 to Abeta1-42, CJD and AD can effectively be differentiated. We conclude that the immunoblot shows disease-specific CSF Abeta peptide patterns in CJD and AD and suppose that measurement of the Abeta peptide pattern seems to be a promising diagnostic tool in the differential diagnosis of dementias.

Clinical findings in sporadic Creutzfeldt-Jakob disease correlate with thalamic pathology.

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 hippocampus in sporadic CJD (sCJD), we studied the distribution and number of PV-immunoreactive neurones in sCJD thalami in order to determine whether damage to them could account for certain clinical findings. Immuno histochemical analysis was performed on the thalami from 21 sCJD patients and five controls. The number of PV+ neurones was counted in the thalamic nuclei and compared with clinical and molecular findings. In sCJD patients, PV+ neurones were significantly reduced in the ventrolateral posterior (VLp), ventrolateral anterior (VLa), anteroventral (AV), lateral dorsal (LD), mediodorsal (MD) and reticular (Re) thalamic nuclei (P < 0.05). The VLp was especially damaged in sCJD patients with homozygosity for methionine at codon 129 and scrapie prion protein (PrP(Sc)) type 1. Patients with typical EEG changes [periodic sharp wave complexes (PSWCs)] and myoclonus had a predominant loss of PV+ cells in the reticular thalamic nucleus. In conclusion, our data support the hypothesis that the damage to PV-immunoreactive neurones determines the generation of certain typical clinical features of CJD, i.e. PSWCs associated with myoclonus.

Mortalidad y causa de muerte en adicciones / Mortality and cause of death in addictions

Se ha investigado la mortalidad y causas de muerte en un grupo de 2.631 pacientes adictos en el curso de 20 años. El pronóstico más favorable (definido por la abstinencia) es el de las adicciones por medicamentos, el peor, el de las adicciones a drogas ilegales. Todas las adicciones estudiadas (abuso y dependencia de alcohol, medicamentos y drogas ilegales) se asocian con un aumento de la mortalidad. El aumento de la mortalidad relativa es muy alto con las drogas ilegales, alto en el alcoholismo y bajo en pacientes adictos a medicamentos. La adicción combinada a alcohol y medicamentos se acompaña de un aumento moderado de la mortalidad, pero de una baja proporción de abstinencia. El aumento de la mortalidad es constante a través de los años. Este incremento es menor si se logra la abstinencia. Los accidentes (incluyendo intoxicaciones) y el suicidio son en todas las adicciones causas de muerte más frecuentes que en la población general