Cognitive function and patient-reported memory problems after radiotherapy for cancers at the skull base: A cross-sectional survivorship study using the Telephone Interview for Cognitive Status and the MD Anderson Symptom Inventory-Head and Neck Module.

BACKGROUND: Using patient-reported and objective assessment tools, we sought to quantify cognitive symptoms and objective cognitive dysfunction in patients irradiated for skull base cancer. METHODS: Participants were assessed using the Telephone Interview for Cognitive Status (TICS) and the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN), with subsequent analysis. RESULTS: Of the 122 participants analyzed, the majority (63%) had no frank detectable cognitive impairment by TICS, with frank impairment in 6%. Overall, mean patient-reported problems with memory (MDASImemory ) was 3.3 (SD ±2.66). On recursive partition analysis, the MDASImemory cutoff point of ≥5 was associated with detectable cognitive impairment by TICS (logworth 1.69; P = .02), yet no MDASImemory threshold was associated with unambiguous absence of impairment by TICS. CONCLUSION: Approximately one third of patients had ambiguous results by TICS assessment, for whom more rigorous testing may be warranted. Moderate to severe levels of patient-reported memory complaints on the MDASI-HN module may have utility as a screening tool for cognitive dysfunction in this population.

Deficient p75 low-affinity neurotrophin receptor expression exacerbates experimental allergic encephalomyelitis in C57/BL6 mice.

We have investigated the role of p75NTR in inflammation in experimental allergic encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS). Induction of EAE in C57/BL6 wild-type mice resulted in expression of p75NTR in endothelial cells in the CNS. In contrast to the clinical manifestation of EAE observed in wild-type C57/BL6 mice, mice deficient for p75NTR (p75NTR knockout mice) developed severe or lethal disease and concomitant increased levels of inflammation in the CNS. Our findings suggest a physiological significant role for p75NTR in CNS endothelial cells during inflammation and involvement in preservation of blood-brain barrier integrity during a severe infiltrative attack.

Monocyte activation and disease activity in multiple sclerosis. A longitudinal analysis of serum MRP8/14 levels.

In active multiple sclerosis (MS) lesions macrophages expressing myeloid related protein (MRP) 8/14 are present. The aim of this study was to determine whether serum levels of MRP8/14 complexes are related to disease activity in MS. In a longitudinal study of 16 relapsing remitting (RR) MS patients that underwent monthly gadolinium diethylentriaminepenta acid (Gd-DTPA) magnetic resonance imaging (MRI), the relation between serum MRP8/14 levels and disease activity was investigated. Patients were participating in a monoclonal antibody study targeting a specific T cell population (Vbeta5.2/5.3+ T-cells). In time, within patients large variations in serum MRP8/14 levels were observed. Serum MRP8/14 levels were not related to changes in clinical disease activity or increase in Gd-DTPA lesion enhancement. Neither did comparison of active (>1 relapse in follow-up period) with inactive (0-1 relapse) MS patients reveal any differences in MRP8/14 levels. Therefore, we conclude that although MRP8/14 expression is a good histopathological marker for monocyte activation, serum levels of these proteins do not correlate with disease activity in RR MS.

Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat.

The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-beta), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-beta treatment reduced lesion volume on diffusion-weighted MRI by 70% (P < 0.01) at 1 day after stroke. IFN-beta attenuated the leakage of contrast agent through the blood-brain barrier (P < 0.005), indicating a better-preserved blood-brain barrier integrity. Both control and IFN-beta-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-beta was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-beta treatment resulted in an 85% reduction (P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-beta almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-beta affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-beta has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.

Interferon-beta prevents cytokine-induced neutrophil infiltration and attenuates blood-brain barrier disruption.

Inflammation can contribute to brain injury, such as that resulting from ischemia or trauma. The authors have previously shown that the cytokine interferon-beta (IFN-beta) affords protection against ischemic brain injury, which was associated with a diminished infiltration of neutrophils and a reduction in blood-brain barrier (BBB) disruption. The goal of the current study was to directly assess the effects of IFN-beta on neutrophil infiltration, with the use of an in vivo assay of neutrophil infiltration with relevance to ischemic brain injury. Intrastriatal injection of recombinant rat cytokine-induced neutrophil chemoattractant-1, a member of the interleukin-8 family (1 microg in 1 microl), triggered massive infiltration of neutrophils and extensive BBB disruption 6 hours later, as measured using immunofluorescence microscopy and magnetic resonance imaging in the rat, respectively. Depleting the animals of neutrophils before interleukin-8 injection prevented BBB disruption. Treatment with IFN-beta (5 x 106 U/kg) almost completely prevented neutrophil infiltration and attenuated BBB damage. Gelatinase zymography showed matrix metalloproteinase-9 expression in the ipsilateral striatum after interleukin-8 injection. Both neutrophil depletion and IFN-beta treatment downregulated matrix metalloproteinase-9. IFN-beta has already been approved for human use as a treatment for the chronic inflammatory disorder multiple sclerosis. The potential value of IFN-beta as a treatment that can attenuate acute brain inflammation is considered.

Heparan sulfate proteoglycans modulate monocyte migration across cerebral endothelium.

Heparan sulfate proteoglycans (HSPGs) are known to participate in a wide range of biological events, including cellular trafficking. In this study we report that in situ cerebral blood vessels highly express HSPGs. Of the syndecan family, syndecan-2 is highly expressed on virtually all brain vessels and syndecan-1 and -3 are only present on larger blood vessels. These endothelial HSPGs have a functional role in monocyte diapedesis across brain endothelium, as assessed in our in vitro adhesion and migration assays. Our data indicate that heparin prevents monocyte adhesion to brain endothelium by interacting solely with the monocyte. Transendothelial migration of monocytes can be prevented by preincubation of brain endothelium with heparin by enzymatic removal of heparan sulphate side chains or by inhibition of cellular sulfation. Blocking of G-protein-dependent signaling in the monocytes prevented monocyte adhesion and migration to similar extent, suggesting that G-dependent signaling may be involved in HSPG-mediated monocyte adhesion and transendothelial migration. Our data demonstrate that brain endothelial HSPGs have a modulatory role in the transendothelial migration of monocytes in a direct and indirect fashion and may therefore contribute to the formation of neuroinflammatory lesions.

Regional and temporal expression patterns of interleukin-10, interleukin-10 receptor and adhesion molecules in the rat spinal cord during chronic relapsing EAE.

Adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mediate leukocyte infiltration into the CNS, in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Because exogenous interleukin-10 (IL-10) inhibits ICAM-1 and VCAM-1 expression and clinical EAE, we hypothesize that endogenous IL-10 signaling may suppress expression of adhesion molecules. In a rat model of chronic relapsing EAE, expression levels of IL-10 and its receptor (IL-10R1), ICAM-1 and VCAM-1 mRNA in the spinal cord are markedly increased, whereas levels of IL-10 mRNA remain relatively low. The temporal pattern of mRNA and protein expression showed marked differences between spinal cord levels. During relapse, IL-10, IL-10R1, ICAM-1, VCAM-1 mRNA levels and neurological scores show positive correlations. We conclude that endogenous IL-10 is not a crucial factor inhibiting adhesion molecule expression in this model.

Interferon-beta directly influences monocyte infiltration into the central nervous system.

Interferon-beta (IFN-beta) has beneficial effects on the clinical symptoms of multiple sclerosis (MS) patients, but its exact mechanism of action is yet unknown. We here suggest that IFN-beta directly modulates inflammatory events at the level of cerebral endothelium. IFN-beta treatment resulted in a marked reduction of perivascular infiltrates in acute experimental allergic encephalomyelitis (EAE), the rat model for MS, which was coupled to a major decrease in the expression of the adhesion molecules ICAM-1 and VCAM-1 on brain capillaries. In vitro, IFN-beta reduced the mRNA levels and protein expression of adhesion molecules of brain endothelial cell cultures and diminished monocyte transendothelial migration. Monocyte adhesion and subsequent migration was found to be predominantly regulated by VCAM-1. These data indicate that IFN-beta exerts direct antiinflammatory effects on brain endothelial cells thereby contributing to reduced lesion formation as observed in MS patients.