Metrological challenges for measurements of key climatological observables: Oceanic salinity and pH, and atmospheric humidity. Part 1: Overview.

Water in its three ambient phases plays the central thermodynamic role in the terrestrial climate system. Clouds control Earth's radiation balance, atmospheric water vapour is the strongest "greenhouse" gas, and non-equilibrium relative humidity at the air-sea interface drives evaporation and latent heat export from the ocean. On climatic time scales, melting ice caps and regional deviations of the hydrological cycle result in changes of seawater salinity, which in turn may modify the global circulation of the oceans and their ability to store heat and to buffer anthropogenically produced carbon dioxide. In this paper, together with three companion articles, we examine the climatologically relevant quantities ocean salinity, seawater pH and atmospheric relative humidity, noting fundamental deficiencies in the definitions of those key observables, and their lack of secure foundation on the International System of Units, the SI. The metrological histories of those three quantities are reviewed, problems with their current definitions and measurement practices are analysed, and options for future improvements are discussed in conjunction with the recent seawater standard TEOS-10. It is concluded that the International Bureau of Weights and Measures, BIPM, in cooperation with the International Association for the Properties of Water and Steam, IAPWS, along with other international organisations and institutions, can make significant contributions by developing and recommending state-of-the-art solutions for these long standing metrological problems in climatology.

A proposal of new diagnostic pathway for fatal familial insomnia.

BACKGROUND: In absence of a positive family history, the diagnosis of fatal familial insomnia (FFI) might be difficult because of atypical clinical features and low sensitivity of diagnostic tests. FFI patients usually do not fulfil the established classification criteria for Creutzfeldt-Jakob disease (CJD); therefore, a prion disease is not always suspected. OBJECTIVE: To propose an update of diagnostic pathway for the identification of patients for the analysis of D178-M129 mutation. DESIGN AND METHODS: Data on 41 German FFI patients were analysed. Clinical symptoms and signs, MRI, PET, SPECT, polysomnography, EEG and cerebrospinal fluid biomarkers were studied. RESULTS: An algorithm was developed which correctly identified at least 81% of patients with the FFI diagnosis during early disease stages. It is based on the detection of organic sleep disturbances, either verified clinically or by a polysomnography, and a combination of vegetative and focal neurological signs and symptoms. Specificity of the approach was tested on three cohorts of patients (MM1 sporadic CJD patients, non-selected sporadic CJD and other neurodegenerative diseases). CONCLUSIONS: The proposed scheme may help to improve the clinical diagnosis of FFI. As the sensitivity of all diagnostic tests investigated but polysomnography is low in FFI, detailed clinical investigation is of special importance.

Gene expression in superior temporal cortex of schizophrenia patients.

We investigated gene expression pattern obtained from microarray data of 10 schizophrenia patients and 10 control subjects. Brain tissue samples were obtained postmortem; thus, the different ages of the patients at death also allowed a study of the dynamic behavior of the expression patterns over a time frame of many years. We used statistical tests and dimensionality reduction methods to characterize the subset of genes differentially expressed in the two groups. A set of 10 genes were significantly downregulated, and a larger set of 40 genes were upregulated in the schizophrenia patients. Interestingly, the set of upregulated genes includes a large number of genes associated with gene transcription (zinc finger proteins and histone methylation) and apoptosis. We furthermore identified genes with a significant trend correlating with age in the control (MLL3) or the schizophrenia group (SOX5, CTRL). Assessments of correlations of other genes with the disorder (RRM1) or with the duration of medication could not be resolved, because all patients were medicated. This hypothesis-free approach uncovered a series of genes differentially expressed in schizophrenia that belong to a number of distinct cell functions, such as apoptosis, transcriptional regulation, cell motility, energy metabolism and hypoxia.

[Hereditary diffuse leukencephalopathy with spheroids: a microgliopathy due to CSF1 receptor impairment]. / Hereditäre diffuse Leukenzephalopathie mit Sphäroiden : Eine Mikrogliopathie durch Fehlfunktion des CSF1-Rezeptors.

Hereditary diffuse leukencephalopathy with spheroids (HDLS) is a rare progressive form of leukodystrophy with variable clinical presentation and little known pathophysiology. Characteristic pathological features at brain biopsy or postmortem can support the diagnosis. The genetic basis of HDLS was elusive until 2011 when mutations in the colony-stimulating factor 1 receptor (CSF1R) gene were identified as the cause. Mutations in the CSF1R gene had previously been associated with tumor development, including hematological malignancies. We report three patients with HDLS who carried missense mutations in the CSF1R gene, two of them novel (p.L582P and p.V383L). Particularly in younger patients with rapid cognitive decline and/or leukencephalopathy of unknown origin, HDLS appears to be more common than previously thought. Various compounds acting on the CSF1 receptor are available from the treatment of hemato-oncological malignancies, so novel therapeutic approaches could be developed for this devastating condition.

Recruitment of neural precursor cells from circumventricular organs of patients with cerebral ischaemia.

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.

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

AIMS: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurones. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. METHODS: We evaluated immunoreactivity (IR) for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. RESULTS: Mean age at death was 68.2 years (range 49-96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of frontotemporal dementia, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein IR was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurones. Aß IR was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. CONCLUSIONS: (i) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; (ii) even minor deviation from these morphological criteria suggests a different disorder; and (iii) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

Influence of the blood-CSF-barrier function on S100B in neurodegenerative diseases.

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 S100BCSF 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 S100BCSF in all diagnoses but with exceptions. Neither S100BCSF 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 S100BCSF 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.

[Molecular biological identification of fungal pathogens in FFPE tissue from cases of cephalic mycosis]. / Molekularbiologischer Erregernachweis aus FFPE-Proben bei zephaler Mykose.

BACKGROUND: Due to the lack of histopathological differentiation the unequivocal identification of fungal pathogens is rarely possible. In order to understand the pathogen spectrum causing cephalic mycosis the use of alternative methods is essential. MATERIAL AND METHODS: In a retrospective study 24 formalin-fixed, paraffin-embedded (FFPE) samples from patients with histologically confirmed cerebral or cephalic mycosis were analyzed with molecular biological methods. RESULTS: In two samples obtained during the patients' lifetime human as well as fungal DNA was detected, making an unambiguous diagnosis possible. For tissue that had been fixed over a longer period, detection of human and fungal DNA was possible merely in 60% and 47 % of the samples, respectively. Most frequently diagnosed were aspergillosis (n = 9), followed by mucormycosis (n = 2) and imported blastomycosis (n = 1). CONCLUSIONS: Using biopsy material a DNA analysis seems promising although only with limited success using brain samples taken at autopsy which have been fixed over a longer period. For unambiguous retrospective diagnostics of pathogens when cephalic mycosis is suspected, the sample extraction for postmortem diagnostics should be performed prior to a long period of formalin fixation.

[German consortium for frontotemporal lobar degeneration]. / Konsortium zur Erforschung der frontotemporalen Lobärdegeneration.

Frontotemporal lobar degeneration (FTLD) is an umbrella term for an aetiologically diverse group of neurodegenerative disorders with prominent lobar cortical atrophy. First this disease group was restricted to Pick's disease or Pick's complex. Several updates of the clinical classification systems were performed and discussed. Currently we summarize the following diseases under the FTLD spectrum: frontotemporal dementia (FTD) as a behavioural variant, primary non-fluent aphasia (PNFA) and semantic dementia as language variants, amyotrophic lateral sclerosis with FTD (ALS-FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).From the pathophysiological aspect major progress was made. Neuropathologically FTLDs are now defined based on the molecular composition of these protein accumulations. A major distinction of tau-associated (FTLD-tau) and TDP43-associated (FTLD-TDP43) and to a lesser extend FUS-associated (FTLD-FUS) has been made. Additional risk genes were described. However from the therapeutic perspective even symptomatic therapy is under discussion. A major aim of our consortium is to develop parameters allowing an early diagnosis and follow-up, thus providing effective and objective parameters for therapeutic strategies.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

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.

MRI in the classical MM1 and the atypical MV2 subtypes of sporadic CJD: an inter-observer agreement study.

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.

Creutzfeldt-Jakob disease in Germany: a prospective 12-year surveillance.

Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disorder with a worldwide incidence of 1-1.5 per million. As in other countries, a CJD surveillance unit with a clinical and neuropathological approach was established in Goettingen (Germany) in 1993. Here we report the epidemiological data from a prospective 12-year surveillance. Since 1993, there has been an increasing incidence of CJD, from 0.7 in 1993 to 1.6 in 2005 with a quite stable level since 1998. During this period, the proportion of patients with MV and VV codon 129 genotype rose, possibly because of better identification of atypical subtypes. Six percent of all patients had a PRNP mutation, mainly D178N-129M (FFI), E200K and V210I. Iatrogenic CJD was a rare phenomenon. No patient infected by cadaveric growth hormone extracts was reported. Furthermore, no variant CJD patient has yet been identified in Germany. Differential diagnoses revealed a variety of neurodegenerative diseases, with Alzheimer's disease in the lead. One-third of the non-CJD patients included in this study suffered from a potentially treatable disorder such as metabolic or inflammatory diseases. The incidence and mortality rates in Germany are similar to those in other European countries. In contrast, however, acquired forms, such as iatrogenic and variant CJD are still rare in Germany or have not yet been identified.

[Molecular neuropathology of Non-Alzheimer dementia]. / Molekulare Neuropathologie der Nicht-Alzheimer-Demenzen.

The increasing life expectancy will cause an increasing share for neurodegenerative and dementing illnesses in the total cost for health care. New developments such as the discovery of TDP-43 as disease protein have opened new viewpoints on frontotemporal dementias, as well as its relation to amyotrophic lateral sclerosis. As pathologists and neuropathologists we are committed to contributing to the progress of clinical diagnosis, which often proves difficult, by standardized post-mortem diagnosis. The diagnostic responsibility will increase with the development of new specific therapeutics and knowledge of contraindications such as the use of neuroleptics in patients suffering from Lewy body dementia. The Reference Center for Neurodegenerative Diseases of the German Society of Neuropathology and Neuroanatomy and the German Brain Bank (Brain-Net) at the Institute for Neuropathology, Ludwig-Maximilians-University Munich, are available for diagnosis in difficult or complex cases.

Pattern of cortical changes in sporadic Creutzfeldt-Jakob disease.

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.

Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study.

BACKGROUND: A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt-Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion-like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND. METHODS: We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI-TOF mass spectrometry. RESULTS: In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over-represented or under-represented in our cohort of patients with sCJD. CONCLUSION: Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.

The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice.

Munc13 proteins form a family of three, primarily brain-specific phorbol ester receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons throughout the rat and mouse CNS, Munc13-3 is almost exclusively expressed in the cerebellum. Munc13-3 mRNA is present in granule and Purkinje cells but absent from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrites, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at parallel fiber-Purkinje cell synapses. To examine the role of Munc13-3 in cerebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 deletion mutants exhibit increased paired-pulse facilitation at parallel fiber-Purkinje cell synapses. In addition, mutant mice display normal spontaneous motor activity but have an impaired ability to learn complex motor tasks. Our data demonstrate that Munc13-3 regulates synaptic transmission at parallel fiber-Purkinje cell synapses. We propose that Munc13-3 acts at a similar step of the synaptic vesicle cycle as does Munc13-1, albeit with less efficiency. In view of the present data and the well established vesicle priming function of Munc13-1, it is likely that Munc13-3-loss leads to a reduction in release probability at parallel fiber-Purkinje cell synapses by interfering with vesicle priming. This, in turn, would lead to increases in paired-pulse facilitation and could contribute to the observed deficit in motor learning.

Evidence of presynaptic location and function of the prion protein.

The prion protein (PrP(C)) is a copper-binding protein of unknown function that plays an important role in the etiology of transmissible spongiform encephalopathies. Using morphological techniques and synaptosomal fractionation methods, we show that PrP(C) is predominantly localized to synaptic membranes. Atomic absorption spectroscopy was used to identify PrP(C)-related changes in the synaptosomal copper concentration in transgenic mouse lines. The synaptic transmission in the presence of H(2)O(2), which is known to be decomposed to highly reactive hydroxyl radicals in the presence of iron or copper and to alter synaptic activity, was studied in these animals. The response of synaptic activity to H(2)O(2) was found to correlate with the amount of PrP(C) expression in the presynaptic neuron in cerebellar slice preparations from wild-type, Prnp(0/0), and PrP gene-reconstituted transgenic mice. Thus, our data gives strong evidence for the predominantly synaptic location of PrP(C), its involvement in the regulation of the presynaptic copper concentration, and synaptic activity in defined conditions.

Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.

The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-)/APLP1(-/-) and APLP2(-/-)/APP(-/-) mice proved lethal early postnatally. Surprisingly, APLP1(-/-)/APP(-/-) mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-)/APP(-/-)/APLP2(+/-) mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicity in vitro.

Prion-induced neuronal damage--the mechanisms of neuronal destruction in the subacute spongiform encephalopathies.

Prion diseases are characterized by the accumulation of a specific disease-associated isoform of the prion protein (PrP), termed PrPSc, which is the main, if not the only, component of the infectious agent termed prion. PrPSc is derived by an autocatalytic post-translational process involving conformational changes from the normal host-encoded isoform of the prion protein, termed PrPC. PrPC is a copper-binding glycoprotein attached to the cell membrane of neurons and other cells by means of a GPI anchor. The pattern of neurodegeneration differs between variants of prion disease and is related to the pattern of PrPSc deposition and differences in susceptibility of different cell types to the disease process. The pattern of PrPSc deposition depends on the strain of the agent and the PrP genotype of the host. Strain properties of prions appear to be related to different pathological conformations of PrPSc. Neuronal cell death is a salient feature in the pathology of prion diseases. Histological and electron microscopical studies have shown that cell death in prion disease occurs by apoptosis. Apoptosis of neuronal cells can also be induced in vitro by exposure to PrPSc or a neurotoxic peptide fragment corresponding to amino acids 106-126 of human prion protein (PrP106-126). Both in vitro and in vivo, the toxicity of PrPSc and PrP fragments appears to depend on neuronal expression of PrPC and on microglial activation. Activated microglial cells release pro-inflammatory cytokines and reactive oxygen species. Cell culture experiments suggest an important role of microglia-mediated oxidative stress in the induction of neuronal cell death. Only limited data are available on direct effects of PrPSc on neuronal cells. Potential effects include increased formation of an aberrant transmembrane form of PrP, termed CtmPrP, and changes in plasma membrane properties. In addition to direct and indirect toxic effects of PrPSc, a loss of function of PrPC may contribute to neuronal cell death. Potential mechanisms include disturbances in cerebral copper metabolism and antioxidative defense mechanisms. A better understanding of the pathogenesis of neuronal cell death in prion diseases may also have important therapeutic implications in the future.

Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies.

A collaborative study of human transmissible spongiform encephalopathies has been carried out from 1993 to 2000 and includes data from 10 national registries, the majority in Western Europe. In this study, we present analyses of predictors of survival in sporadic (n = 2304), iatrogenic (n = 106) and variant Creutzfeldt-Jakob disease (n = 86) and in cases associated with mutations of the prion protein gene (n = 278), including Gerstmann-Sträussler-Scheinker syndrome (n = 24) and fatal familial insomnia (n = 41). Overall survival for each disease type was assessed by the Kaplan-Meier method and the multivariate analyses by the Cox proportional hazards model. In sporadic disease, longer survival was correlated with younger age at onset of illness, female gender, codon 129 heterozygosity, presence of CSF 14-3-3 protein and type 2a prion protein type. The ability to predict survival based on patient covariates is important for diagnosis and counselling, and the characterization of the survival distributions, in the absence of therapy, will be an important starting point for the assessment of potential therapeutic agents in the future.