STAT3-Ser/Hes3 Signaling: A New Molecular Component of the Neuroendocrine System?

The endocrine system involves communication among different tissues in distinct organs, including the pancreas and components of the Hypothalamic-Pituitary-Adrenal Axis. The molecular mechanisms underlying these complex interactions are a subject of intense study as they may hold clues for the progression and treatment of a variety of metabolic and degenerative diseases. A plethora of signaling pathways, activated by hormones and other endocrine factors have been implicated in this communication. Recent advances in the stem cell field introduce a new level of complexity: adult progenitor cells appear to utilize distinct signaling pathways than the more mature cells in the tissue they co-reside. It is therefore important to elucidate the signal transduction requirements of adult progenitor cells in addition to those of mature cells. Recent evidence suggests that a common non-canonical signaling pathway regulates adult progenitors in several different tissues, rendering it as a potentially valuable starting point to explore their biology. The STAT3-Ser/Hes3 Signaling Axis was first identified as a major regulator of neural stem cells and, subsequently, cancer stem cells. In the endocrine/neuroendocrine system, this pathway operates on several levels, regulating other types of plastic cells: (a) it regulates pancreatic islet cell function and insulin release; (b) insulin in turn activates the pathway in broadly distributed neural progenitors and possibly also hypothalamic tanycytes, cells with important roles in the control of the adrenal gland; (c) adrenal progenitors themselves operate this pathway. The STAT3-Ser/Hes3 Signaling Axis therefore deserves additional research in the context of endocrinology.

Creutzfeldt-Jakob disease: comparative analysis of MR imaging sequences.

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.

Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer's disease.

Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimer's disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), Abeta42, Abeta40 and S-100B protein, using a set of commercially available assays. Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. Abeta42 and Abeta40 remained relatively stable during follow-up but we found a slight increase of the median Abeta42 level in DLB, whereas in AD, Abeta42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases. The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD. Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.

Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada.

BACKGROUND: An international study of the epidemiologic characteristics of Creutzfeldt-Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland. METHODS: Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes. RESULTS: Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK. CONCLUSIONS: This study has established overall epidemiologic characteristics for Creutzfeldt-Jakob disease (CJD) of all types in a multinational population-based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.

Immunoglobulins and virus-specific antibodies in patients with Creutzfeldt-Jakob disease.

OBJECTIVES: Cerebrospinal fluid (CSF) pattern in patients with neuropathologically diagnosed Creutzfeldt-Jakob disease was analyzed. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Interferon beta-1b modulates serum sVCAM-1 levels in primary progressive multiple sclerosis.

Endothelial activation is a key feature of multiple sclerosis (MS) pathogenesis. It is modulated by interferon beta-1b (IFNB-1b) treatment in relapsing-remitting MS (RRMS) patients. This particular pharmacodynamic effect still has to be proven in primary progressive MS (PPMS). In the current study, serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin were analyzed longitudinally in 18 PPMS patients before, during and after 12 months of treatment with IFNB-1b. During drug therapy there was a significant early and sustained increase of sVCAM-1 (overall P < 0.0001). Flu-like symptoms induced by IFNB-1b and also concomitant infections were associated with higher sVCAM-1 levels. Neutralizing antibodies to IFNB-1b were associated with lower sVCAM-1 levels. In conclusion, IFNB-1b modulates the adhesion cascade in patients with PPMS in a similar way it does in RRMS. Nevertheless, a clinical effect of IFNB in PPMS still has to be proven in a randomized controlled clinical trial.

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.

Sporadic Creutzfeldt-Jakob disease: magnetic resonance imaging and clinical findings.

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.

Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study.

BACKGROUND: In cell culture experiments, flupirtine maleate (FLU), a triaminopyridine compound, was able to protect neuronal cells from apoptotic cell death induced by prion protein fragments and beta-amyloid peptides. As FLU is a clinically safe drug, the authors started a double-blind placebo-controlled study in patients with Creutzfeldt-Jakob disease (CJD). METHODS: Twenty-eight patients with CJD were randomized to an oral treatment with either FLU (n = 13) or matching placebo (PLA; n = 15). For inclusion and continuing the study, the patients had to achieve at least 50% in two of the subscales of the dementia tests employed. A battery of standardized questionnaires was employed to monitor the progression of the disease. The main outcome variable was the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog); the difference between baseline and the best score under treatment was defined as the primary efficacy variable for hypothesis testing. RESULTS: CJD types were homogeneously distributed among the treatment groups. Patients treated with FLU showed significantly less deterioration in the dementia tests than patients treated with PLA. The mean change in ADAS-Cog (baseline to best) was +8.4 (+/-15.3) in the FLU group and +20.6 (+/-15.1) in the PLA group (p = 0.02, one-sided t-test). CONCLUSIONS: FLU has beneficial effects on cognitive function in patients with CJD. These positive results also may suggest a treatment potential of FLU in other neurodegenerative disorders. However, further studies are necessary.

CSF lactate dehydrogenase activity in patients with Creutzfeldt-Jakob disease exceeds that in other dementias.

The diagnosis of Creutzfeldt-Jakob disease (CJD) is still made by exclusion of other dementias. We now evaluated lactate dehydrogenase (LDH) in the cerebrospinal fluid (CSF) as a possible additional diagnostic tool. CSF LDH levels of patients with CJD (n = 26) were compared with those in other dementias (n = 28). LDH isoenzymes were determined in a subset (n = 9). Total LDH and isoenzyme LDH-1 were significantly higher, whereas the fractions of LDH-2 and LDH-3 were significantly lower in CJD patients. We conclude that in addition to established CSF parameters, LDH and its isoenzymes might serve as a further help to discriminate between CJD and other dementias.

The macrophage activity marker sCD14 is increased in patients with multiple sclerosis and upregulated by interferon beta-1b.

The soluble form of the CD14 molecule (sCD14), a macrophage activity marker, was measured in the plasma of 17 patients with primary progressive multiple sclerosis (PPMS) and 20 patients with relapsing remitting MS (RRMS). In patients with PPMS, sCD14 levels were determined before and after treatment with interferon beta (IFNB). In both PPMS and in RRMS, sCD14 levels were significantly elevated compared to healthy controls. In patients with PPMS, sCD14 levels increased significantly during the first 3 months of IFNB therapy, then slightly decreased, but still remained elevated compared with levels before therapy. Therefore, the elevated sCD14 levels may be a marker in evaluating biological response to IFNB therapy.

Sporadic Creutzfeldt-Jakob disease and surgery: a case-control study using community controls.

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.

[Epidemiology and clinical symptomatology of Creutzfeldt-Jakob disease]. / Epidemiologie und klinische Symptomatik der Creutzfeldt-Jakob-Krankheit.

OBJECTIVE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease.

BACKGROUND: Diagnosis of Creutzfeldt-Jakob disease (CJD) is made according to the typical clinical picture and can be supported by a positive 14-3-3 CSF immunoblot. Promising results for the diagnostic sensitivity and specificity of tau-protein measurement in CSF already have been described in a smaller group of patients. Both tests in a larger group of patients with the differential diagnosis of CJD were evaluated. METHODS: CSF of 297 patients under the differential diagnosis of CJD (109 definite, 55 probable, 39 possible; 85 others, 1 iatrogenic, 8 genetic), 23 nondemented control subjects, and 15 non-CJD patients with positive 14-3-3 immunoblots were analyzed. The 14-3-3 immunoblot bands were semiquantitatively rated as strong, medium, and weak. Tau-protein was analyzed using a commercially available ELISA. In addition, patients were neuropathologically classified according to prion protein type and polymorphism at codon 129. RESULTS: A diagnostic sensitivity of 94%, a diagnostic specificity of 90%, and a positive predictive value of 92% were achieved for tau-protein at a cut-off of 1,300 pg/mL. These results are comparable with those of the 14-3-3 immunoblot. For patients with type II prion protein and methionine/valine or valine/valine polymorphism at codon 129, tau-protein has a higher diagnostic sensitivity than 14-3-3 protein. Tau-protein levels were significantly higher in patients with higher-rated 14-3-3 immunoblot bands. CONCLUSION: The differential diagnostic significance of the 14-3-3 immunoblot is similar to that of the tau-protein ELISA. The advantage of the tau-protein ELISA is that it is easy to use in routine laboratories. Patients with a negative 14-3-3 immunoblot already have measurable tau-protein levels. This increases information on 14-3-3-negative patients with CJD and especially on patients with other diseases.

Polymorphisms within the prion-like protein gene (Prnd) and their implications in human prion diseases, Alzheimer's disease and other neurological disorders.

Only 10% of human transmissible spongiform encephalopathies (TSEs) are associated with mutations of the Prnp region encoding the prion protein (PrP). Recently, the murine PrP-like protein doppel (Dpl) was described and was shown to be overexpressed in certain strains of PrP knockout mice and to cause neurological diseases such as ataxia and Purkinje cell loss. To answer the question of whether there are any polymorphisms within the PrP-like protein gene (Prnd) that might cause or be involved in the development of TSEs, we investigated the complete open reading frame of the human Prnd gene from 58 patients who had died of genetic or sporadic Creutzfeldt-Jakob disease (CJD), Alzheimer's disease or other neurological disorders and from 111 controls. We found five new polymorphisms and one frame shift mutation. One silent polymorphism, which does not lead to an altered amino acid sequence, was also observed. Statistical analysis revealed a significant difference in the distribution of the Prnd genotype at codon 174 between sporadic CJD patients and healthy controls.