Mechanism of glial activation by S100B: involvement of the transcription factor NFkappaB.

Compelling evidence links chronic activation of glia and the subsequent cycle of neuroinflammation and neuronal dysfunction to the progression of neurodegeneration in disorders such as Alzheimer's disease (AD). S100B, a glial-derived cytokine, is significantly elevated in the brains of AD patients and high concentrations of S100B are believed to be detrimental to brain function. As a first step toward elucidating the mechanisms by which S100B might be serving this detrimental role, we examined the mechanisms by which S100B stimulates glial inducible nitric oxide synthase (iNOS), an oxidative stress related enzyme that has been linked to neuropathology through the production of neurotoxic peroxynitrite. We report here that S100B stimulates iNOS in rat primary cortical astrocytes through a signal transduction pathway that involves activation of the transcription factor NFkappaB. NFkappaB activation was demonstrated by nuclear translocation of the p65 NFkappaB subunit, stimulation of NFkappaB-specific DNA binding activity, and stimulation of NFkappaB-dependent transcriptional activity. Furthermore, S100B-induced iNOS promoter activation was inhibited upon mutation of the NFkappaB response element in the promoter, and transfection of cells with an NFkappaB inhibitor blocked S100B-induced iNOS promoter activation and nitric oxide production. These studies define a signal transduction pathway by which S100B activation of glia could participate in the generation of oxidative stress in the brain.

Volumetric neuroimaging in Usher syndrome: evidence of global involvement.

Usher syndrome is a group of genetic disorders consisting of congenital sensorineural hearing loss and retinitis pigmentosa of variable onset and severity depending on the genetic type. It was suggested that the psychosis of Usher syndrome might be secondary to a metabolic degeneration involving the brain more diffusely. There have been reports of focal and diffuse atrophic changes in the supratentorial brain as well as atrophy of some of the structures of the posterior fossa. We previously performed quantitative analysis of magnetic resonance imaging studies of 19 Usher syndrome patients (12 with type I and 7 with type II) looking at the cerebellum and various cerebellar components. We found atrophy of the cerebellum in both types and sparing of cerebellar vermis lobules I-V in type II Usher syndrome patients only. We now have studied another group of 19 patients (with some overlap in the patients studied from the previous report) with Usher syndrome (8 with type I, 11 with type II). We performed quantitative volumetric measurements of various brain structures compared to age- and sex-matched controls. We found a significant decrease in intracranial volume and in size of the brain and cerebellum with a trend toward an increase in the size of the subarachnoid spaces. These data suggest that the disease process in Usher syndrome involves the entire brain and is not limited to the posterior fossa or auditory and visual systems.

Cavum septi pellucidi and cavum vergae in normal and developmentally delayed populations.

Recent studies have shown that the persistence of the cavum septi pellucidi beyond the neonatal period is a marker of cerebral dysgenesis. It has been suggested that the finding of a persistent cavum vergae is also a marker of disturbed brain development. In order to investigate this hypothesis we reviewed 161 brain magnetic resonance imaging scans from normal individuals for the presence of cavum septi pellucidi or cavum vergae, or both. In the 34 prospectively obtained normal adults, there were no individuals with either a cavum septi pellucidi or cavum vergae. In the "defined" normal subjects 3 of 127 individuals (2.4%) had a cavum septi pellucidi whereas a cavum vergae was noted in 26 of 127 (20.5%). We next reviewed the neuroimaging studies of 249 children and adults evaluated for mental retardation or developmental delay. A cavum septi pellucidi was found in 38 of 249 (15.3%) and a cavum vergae in 48 of 249 (19.3%) of these patients. A cavum septi pellucidi and cavum vergae were found together in 19 of 249 (7.6%). We interpret these data as showing that the cavum septi pellucidi is rarely seen in normal individuals although the cavum vergae is seen with the same frequency in normal and retarded populations. Thus we conclude that the cavum septi pellucidi serves as a significant marker of cerebral dysfunction manifested by neurodevelopmental abnormalities while the cavum vergae alone does not identify individuals at risk for cognitive delays.