The precision of T1 hypointense lesion volume quantification in multiple sclerosis treatment trials: a multicenter study.

The volume of hypointense lesions on T1 weighted brain MRI represents an increasingly used MR endpoint in phase III MS treatment trials. In this study we evaluated the reproducibility of hypointense T1 lesion volume quantification in a cohort of Multiple Sclerosis (MS) patients. The gadolinium enhanced T1 weighted brain MR images of 33 MS patients from three European centers were used in this study. These images were acquired as part of a phase III trial of interferon beta-1b in secondary progressive MS. The MRI machine manufacturers and imaging parameters varied according to the MRI acquisition center. Three experienced observers used a semi-automated local thresholding technique to quantify the hypointense T1 lesion volume on two occasions, separated by a delay. The intra and inter observer coefficients of variation were 3.7% and 4.9% respectively, with similar values derived for images obtained at all three sites. There was a generally high level of agreement between the lesion volumes obtained by the three raters. However, a modest but significant measurement drift was identified between the first and second sessions for one of the three raters, highlighting the very real possibility of measurement drift even for experienced observers. Our results support the increasing role for T1 hypointense lesion volume as an outcome measure in multicenter phase III MS treatment trials. Multiple Sclerosis (2000) 6 237 - 240

A different isoform of the transport protein mutated in the glycogen storage disease 1b is expressed in brain.

There are differences in the kinetic properties of the liver and brain microsomal glucose-6-phosphate transport systems suggesting the possibility of tissue specific isoforms. The availability of a human liver cDNA sequence which is mutated in patients with deficiencies of liver microsomal glucose-6-phosphate transport (glycogen storage disease 1b) made it possible to determine if a brain isoform exists. Northern blots of liver and brain RNA revealed that the mRNA of the brain form is slightly longer than the liver one. Isolation and sequencing of the respective human brain cDNA revealed that the brain protein has an additional 22 amino acid sequence.

A comparison of the renal and hepatic microsomal glucose-6-phosphatase enzymes.

The liver glucose-6-phosphatase enzyme has been extensively characterized and relatively little is known about the renal microsomal glucose-6-phosphatase enzyme. The reason for lack of study of the renal glucose-6-phosphatase enzyme is that it has been assumed to be the same as the liver enzyme. Immunoblotting with antibodies raised against the liver enzyme revealed differences in apparent molecular weight and antigenicity between the liver and kidney glucose-6-phosphatase enzyme proteins. Characterization of the activity of the renal glucose-6-phosphatase enzyme also showed that it is regulated differently to the liver enzyme in some metabolic states. This implies that the renal and liver glucose-6-phosphatase enzymes may have different roles.

A role for astrocytes in glucose delivery to neurons?

The present paper examines the possible role of astrocytes in the delivery of glycogen-derived glucose for neuronal metabolism. Such a process would require astrocytic expression of glucose-6-phosphatase. The degree and significance of brain expression of glucose-6-phosphatase (EC 3.1.3.9) has been a subject of controversy. Published immunohistochemical data are consistent with expression of glucose-6-phosphatase by astrocytes, both in vivo and in vitro. In this paper additional confirmation of the expression of glucose-6-phosphatase mRNA in rat brain is presented. Although cultured astrocytes demonstrate glucose-6-phosphatase activity in vitro under assay conditions, there is very limited in vitro evidence that this activity confers a glucose-export capacity on astrocytes. Under most conditions in vitro, lactate export predominates, however this may relate to aspects of the in vitro phenotype. Data relating to astrocytic glucose and lactate export are considered in the context of hypotheses of trafficking by astrocytes of substrates for neuronal metabolism, hypotheses that imply and require compartmentation of these substances, in contrast with current formulations of glucose transport into and within brain that imply no glucose compartmentation. Microdialysis studies of the properties of the brain extracellular fluid (ECF) glucose pool in the freely moving rat were performed seeking evidence of glucose compartmentation. Results of these studies do imply compartmentalisation of brain glucose, and are consistent with a model envisaging the majority of glucose reaching the neuron via the astrocytic intracellular space and the ECF. In addition, such studies provide evidence that rises in ECF glucose concentration are not the direct result of local recruitment of cerebral blood flow, but suggest the influence of intermediate, astrocyte-based mechanisms. Astrocytic glucose-6-phosphatase may permit astrocytes to modulate the trans-astrocytic flux of glucose to adjacent neurons in response to signals reflecting increased neuronal demand.