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Objectives S100B was proposed to be a CSF and blood biomarker in a number of neurological diseases. The route of S100B to the CSF and the blood in neurodegenerative diseases is unclear. To assess the impact of the physiological or impaired blood- CSF-barrier ( BCSFB) function on S100B concentrations in CSF and serum, we analysed S100B in correlation of the albumin quotient. Materials and methods S100Bserum and S100 BCSF were quantified in samples from patients with a variety of neurological diseases using an immunoluminometric assay (Sangtec LIA-mat). Measures were analysed for a potential relation to the CSF/serum-albumin quotient ( Qalb), which indicates the BCSFB functionality. Results We reasserted increased S100B concentrations in CSF and serum of CJD patients. Elevated S100Bserum correlated with elevated S100 BCSF in all diagnoses but with exceptions. Neither S100 BCSF nor S100Bserum did correlate with Qalb, even when the BCSFB function was progressively impaired as demonstrated by increased Qalb. Conclusions The lack of correlation between Qalb and S100 BCSF is typically seen for proteins which are brain derived. Therefore, we propose that S100B enters the blood with the bulk flow via Pacchioni's granules and along the spinal nerve sheaths. [ABSTRACT FROM AUTHOR]

Aims Adult neurogenesis is well described in the subventricular zone of the lateral ventricle walls and in the subgranular zone of the hippocampal dentate gyrus. However, recent studies indicate that self-renewal of neural stem cells ( NSCs) is not restricted to these niches, but that diverse areas of the adult brain are capable of generating new neurones and responding to various pathological alterations. In particular, NSCs have been identified in circumventricular organs ( CVOs) of the adult mouse brain. Methods In order to detect possible neural stem or progenitor cells in CVOs of the human brain, we analysed post mortem human brain tissue from patients without neuropathological changes ( n = 16) and brains from patients with ischaemic stroke ( n = 16). Results In all analysed CVOs (area postrema, median eminence, pineal gland and neurohypophysis) we observed cells with expression of early NSC markers, such as GFAP, nestin, vimentin, OLIG2 and PSA-NCAM, with some of them coexpressing Ki67 as a marker of cell proliferation. Importantly, stroke patients displayed an up to fivefold increase with respect to the relative number of Ki67- and OLIG2-expressing cells within their CVOs. Conclusions Our findings are compatible with a scenario where CVOs may serve as a further source of NSCs in the adult human brain and may contribute to neurogenesis and brain plasticity in the context of brain injury. [ABSTRACT FROM AUTHOR]

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene ( MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer’s disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly ( P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% ( P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration – whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell. [ABSTRACT FROM AUTHOR]

Mutations in the tern gene cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 characterized by filamentous tau protein deposits. Here we describe the clinical and neuropathological features of a case from a newly identified family with an intron 10+ 3- splice site mutation in the tau gene. The proband presented with severe personality changes and stereotyped speech followed by parkinsonian symptoms. He died at age 56 after a disease duration of approximately 6 years. At autopsy, there was marked frontotemporal degeneration with abundant tau-immunoreactive neuronal and glial inclusions widespread in the cortex and brainstem. RT- PCR analysis revealed a 3.7-fold increase of tau transcripts with exon 10, resulting in an 1.7-fold higher expression level of 4-repeat tau isoforms in soluble tau fractions when compared to control brains and exclusively 4-repeat tau isoforms in the sarcosyl-insoluble tau fractions. In accordance with the hypothesis that the overexpression leads to saturation of microtubule binding sites and an increase of unbound 4-repeat tau isoforms which assemble into filaments, the neuronal and glial inclusions in this case were exclusively composed of 4-repeat tau isoforms. The clinical and neuropathological data of this family are compared with results from the two other published families with the intron 10+3 mutation, the MSTD and the SOT 254 family. [ABSTRACT FROM AUTHOR]

Jacobi C, Arlt S, Reiber H, Westner I, Kretzschmar HA, Poser S, Zerr I. Immunoglobulins and virus-specific antibodies in patients with Creutzfeldt–Jakob disease.Acta Neurol Scand 2005: 111: 185–190.© Blackwell Munksgaard 2005.Cerebrospinal fluid (CSF) pattern in patients with neuropathologically diagnosed Creutzfeldt–Jakob disease was analyzed.Routine tests included white blood cells count, protein, albumin, immunoglobulins and the presence of oligoclonal immunoglobulin G (IgG) in the CSF as well as the calculation of intrathecal synthesis of immunoglobulins by standard methods. In addition, antibodies against neurotropic viruses such as measles, rubella, varicella zoster and herpes simplex were measured and the specific antibody index was calculated.A blood–CSF barrier dysfunction was observed in six of 25 cases. In CSF/serum quotient diagrams, no patient had intrathecally synthesized immunoglobulins, but in two of 25 patients oligoclonal bands were detected. Two patients had intrathecally synthesized antibodies against varicella zoster and three against herpes simplex virus.In conclusion, in the routine diagnosis, the CSF in CJD is normal in most cases. In some patients, abnormalities include the blood–CSF barrier dysfunction, mild pleocytosis, oligoclonal bands and intrathecally synthesized viral antibodies. [ABSTRACT FROM AUTHOR]

U. Schüller, F. Schober, H. A. Kretzschmar and J. Herms (2004)Neuropathology and Applied Neurobiology, doi:10.1111/j.1365-2990.2004.00553.xBcl-2 expression inversely correlates with tumour cell differentiation in medulloblastomaMedulloblastoma (MB) is a cerebellar primitive neuroectodermal tumour that occurs predominantly in childhood. It can be mainly divided into classical and desmoplastic tumours, but differential diagnosis is often difficult. Patients’ prognosis is poor and neuropathological markers that reliably predict outcome are still missing. In a series of 104 MBs including 80 tumours of the classical and 24 tumours of the desmoplastic variant we studied the number of apoptotic figures and the expression of the proto-oncogene bcl-2, an anti-apoptotic protein known to affect tumour cell proliferation. We observed a strong correlation between the expression of bcl-2 with patients’ age (P < 0.001) as well as with the desmoplastic subtype (P < 0.001). Here, protein expression was found to be restricted to internodular, less differentiated, highly proliferative areas. In classical MB, bcl-2 was detected only in 23% of cases and was highly inversely correlated with the expression of synaptophysin (P < 0.001) indicating that bcl-2 is predominantly expressed by undifferentiated classical MB. With regard to prognosis the expression of bcl-2 tended to correlate with poor outcome in classical MB but not in desmoplastic MB, although not to a statistically significant extension (P = 0.06). On the other hand, a high number of apoptotic figures in the tumour tissue was found to indicate poor prognosis independent of the histological subtype (P < 0.05). [ABSTRACT FROM AUTHOR]

Abstract: 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 β, γ, ε, and η are present in the CSF of patients with CJD and can be used to differentiate other dementias. 14-3-3η also gave a baseline signal in all patients with other dementias, including six patients with Alzheimer's disease. The presence of 14-3-3η 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 β, γ, and ε should be considered for the neurochemical differentiation of CJD from other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Bovine spongiform encephalopathy (BSE) has been described as an epidemic central nervous disorder in cattle from the United Kingdom. The disease is thought to have emerged by an interspecies transmission of the scrapie agent of sheep to cattle, after feeding scrapie-contaminated meat and bone meal (MBM). The disease has caused substantial economic losses for the British cattle industry. Because of strict veterinary regulations for the import of adult British cattle by the European Union and for MBM by most of the member states the spread of BSE to continental Europe could be efficiently controlled, and only few cases have been described outside the UK. Here we report the first German case of BSE diagnosed in a Scottish Highland cow. The affected cow was imported into Germany before the import ban for cattle from the UK was implemented. BSE was confirmed by histopathology, immunohistochemistry, animal experiments, immunoblotting and by electron microscopic detection of scrapie-associated fibrils (SAFs). Zusammenfassung Dieser Artikel beschreibt den Nachweis des ersten BSE-Falles in der Bundesrepublik Deutschland. Bei dem Rind handelte es sich um ein aus Großbritannien vor dem Verbringungsverbot eingeführtes Scottish-Highland-Rind, das zunächst unter zentralnervösen Symptomen erkankte und später verendete. Nachdem das Vorliegen anderer bakterieller oder virusbedingter Erkrankungen (u.a. Listeriose, Aujeszkysche Krankheit, Tollwut) ausgeschlossen worden war, wurden bei der anschließenden histopathologischen Untersuchung die typischen Veränderungen einer spongiformen Enzephalopathie festgestellt und von vier weiteren Pathologen bestätigt. Da das Gehirn zunächst Formalin-fixiert worden war, erbrachten der Nachweis der Scrapie-assoziierten Fibrillen und der Immunoblot zur Feststellung von PrPSc-bzw PrPBSE-negative Ergebnisse. Unabhängig davon wurden 12 weibliche C57Bl/Han-Mäuse intrazerebral und intraperitoneal mit Hirnhomogenat infiziert. Eine Kontrollgruppe erhielt Hirnhomogenat eines gesunden Tieres. Nach einer Inkubationszeit von etwa 520 Tagen erkrankten vier Mäuse der mit BSE-Material infizierten Versuchsgruppe. Bei zweien dieser Tiere wurden durch histopathologische und immunhistochemische Untersuchungen die für BSE-typischen spongiformen Enzephalopathien sowie 'Scrapie-associated Fibrils (SAFs)' festgestellt werden. Die eindeutige Bestätigung der Diagnose wurde durch den Immunoblot-Nachweis von PrPBSE 27-30kDa im Gehirn der erkrankten Mäuse erbracht. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The cellular isoform of the prion protein (PrPC) is a cell surface glycoprotein attached to the outer leaflet of the plasma membrane by a glycosylphosphatidyl-inositol (GPI) anchor. PrPC is involved in the pathogenesis of prion diseases and has recently been shown to play a role in haemopoietic cell activation and proliferation. We have used the PrPC-specific monoclonal antibody (mAb) 3F4 in a flow cytometry approach to analyse the constitutive expression of PrPC on human peripheral blood (PB) cell populations from patients with paroxysmal nocturnal haemoglobinuria (PNH), which are characterized by a deficiency of GPI-linked cell surface proteins. Comparable PrPC expression levels (P > 0.05), quantified as mean fluorescent intensity, were measured on lymphocytes isolated from normal donors (n = 10) and patients with PNH (n = 5), whereas PNH PB monocytes and granulocytes exhibited substantially lower PrPC surface immunoreactivity than their normal counterparts (P < 0.05). More detailed histogram analyses of the PNH PB leucocytes revealed that PrPC was absent in PNH granulocytes, but was normally expressed in lymphocytes from four out of five patients. However, in one patient a bimodal distribution of 3F4 mAb staining was observed, indicating the presence of a PrPC-deficient lymphocyte subpopulation. In conclusion, our results show that PNH haemopoietic cells are deficient in cell surface-bound PrPC.

The cellular isoform of the prion protein (PrPC) is a cell surface glycoprotein that has recently been shown to play a role in haemopoietic cell activation and proliferation. We have characterized the constitutive expression of PrPC on human peripheral blood (pB) cell populations, using PrP-specific antibodies in a multiparameter flow cytometry approach. We found that T cells, NK cells and monocytes exhibit similar PrPC levels, whereas PrPC surface staining on B cells was significantly lower and was virtually absent on granulocytes. Within the T-cell compartment, CD8+ cells showed a significantly higher PrPC expression than CD4+ cells. Similarly, CD3+ cells co-expressing the activation marker CD56 (N-CAM) exhibited significantly higher PrPC expression levels than their CD56- counterparts. Culture of CD14+ pB monocytes for 12-48 h in the presence of interferon gamma (IFN-gamma) resulted in a significant increase in PrPC expression in a time- and concentration-dependent manner. This effect was partially abrogated by the addition of the metabolic inhibitor cycloheximide, indicating the role of protein synthesis in this process. Our results show that PrPC expression on human haemopoietic cells correlates with the activation and developmental status of these cells, suggesting an important functional role of PrPC in the haemopoietic system.

Alzheimer's disease and prion diseases such as Creutzfeldt-Jakob disease are caused by as yet undefined metabolic disturbances of normal cellular proteins, the amyloid precursor protein and the prion protein (PrP). Synthetic fragments of both proteins, beta-amyloid 25-35 (betaA25-35) and PrP106-126, have been shown to be toxic to neurons in culture. Cell death in both cases occurs by apoptosis. Here we show that there are considerable differences in the mechanisms involved. Thus, PrP106-126 is not toxic to cortical cell cultures of PrP knockout mouse neurons whereas betaA25-35 is. The toxicity of both peptides involves Ca2+ uptake through voltage-sensitive Ca2+ channels but only PrP106-126 toxicity involves the activity of NMDA receptors. The toxicity of betaA25-35, but not PrP106-126, is attenuated by the action of forskolin. These results indicate that PrP106-126 and PA25-35 induce neuronal apoptosis through different mechanisms.