Nadine Wilczak

GFAP and S100B in the acute phase of mild traumatic brain injury

Objective: The biomarkers glial fibrillary acid protein (GFAP) and S100B are increasingly used as prognostic tools in severe traumatic brain injury (TBI). Data for mild TBI are scarce. This study aims to analyze the predictive value of GFAP and S100B for outcome in mild TBI and the relation with imaging. Methods: In 94 patients biomarkers were determined directly after admission. Collected data included injury severity, patient characteristics, admission CT, and MRI 3 months postinjury. Six months postinjury outcome was determined with Glasgow Outcome Scale Extended (GOSE) and return to work (RTW). Results: Mean GFAP was 0.25 μg/L (SD 1.08) and S100B 0.54 μg/L (SD 1.18). In 63% GFAP was not discernible. GFAP was increased in patients with an abnormal CT (1.20 μg/L, SD 2.65) compared to normal CT (0.05 μg/L, SD 0.17, p < 0.05). Also in patients with axonal injury on MRI GFAP was higher (0.65 μg/L, SD 0.91 vs 0.07 μg/L, SD 0.2, p < 0.05). GFAP was increased in patients with incomplete RTW compared to complete RTW (0.69 μg/L, SD 2.11 vs 0.12 μg/L, SD 0.38, p < 0.05). S100B was not related to outcome or imaging studies. In multivariate analysis GFAP was not predictive for outcome determined by GOSE and RTW. Conclusions: A relation between GFAP with imaging studies and outcome (determined by RTW) was found in contrast to S100B. As the positive predictive value of GFAP is limited in this category of TBI patients, this biomarker is not suitable for prediction of individual patient outcome.

Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors

Background: In MS, T cells reactive to myelin proteins can cross the blood–brain barrier and release proinflammatory cytokines, such as interferon γ. These can induce glial cells to express class II major histocompatibility complex (MHC) molecules, which are required to present myelin antigens to the T cells in order to mount a proper autoimmune response. Both microglia and astrocytes can function as antigen-presenting cells. In contrast to microglia, endogenous suppressors, including norepinephrine, regulate astrocytic class II MHC expression. The effects of norepinephrine are mediated through activation of β2 adrenergic receptors. Objective: To investigate β2 adrenergic receptors in astrocytes in MS. Methods: Immunocytochemical techniques were applied in postmortem brain tissue from 10 patients with MS, three patients with a cerebral infarction, and six controls, and in spinal cord from three patients with ALS. Results: β2 adrenergic receptors were visualized on astrocytes in white matter of controls, and they were prominently expressed in reactive astrocytes at the boundary of cerebral infarctions and in the lateral corticospinal tract in ALS. In MS, β2 adrenergic receptors could neither be visualized on astrocytes in normal-appearing white matter nor in reactive astrocytes in chronic active and inactive plaques, whereas they were normally present on neurons. MHC class II–positive astrocytes were only visualized in chronic active plaques. Conclusions: Because astrocytic β2 adrenergic receptors are involved in suppressing inducibility of MHC class II molecules, we suggest that their lack of expression may play an important role in the induction or perpetuation of autoimmune reactions in MS.

Free insulin-like growth factor (IGF)-I and IGF binding proteins 2, 5, and 6 in spinal motor neurons in amyotrophic lateral sclerosis

BACKGROUND Insulin-like growth factor-I (IGF-I) is a potent survival factor for motor neurons and is being investigated as possible therapeutic agent for amyotrophic lateral sclerosis. However, very little information is available on the components of the IGF-I system in this disease. Insulin-like growth factor binding proteins (IGFBPs) play an important part in regulating the bioavailability of IGF-I. METHODS We investigated the components of the IGF-I system in spinal cord sections of ten patients with amyotrophic lateral sclerosis and in ten controls without neurological disease. IGF-I was studied by western immunoblotting. IGFBPs and IGF-I receptors were investigated by immunohistochemistry and Western immunoblotting. FINDINGS Total IGF-I in ventral horn homogenates did not differ between patients and controls. However, free IGF-I was 53% lower in patients than in controls. Compared with controls, immunoreactivity in the spinal motor neurons of patients with amyotrophic lateral sclerosis was 64% higher for IGFBP2, 46% higher for IGFBP5, and 33% higher for IGFBP6, with upregulation of IGF-I receptors. Immunoreactivity for IGFBPs1, 3, and 4 did not differ between patients and controls. INTERPRETATION In the ventral horns of patients, free IGF-I is reduced, which could be because of specific increases in IGFBPs 2, 5, and 6 in spinal motor neurons. This abnormality might have an important role in the processes leading to motor neuron death, and should be taken into account when developing treatments aimed to stimulate IGF-I receptors in motor neurons.

Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2.

Astrocytes in active lesions of multiple sclerosis (MS) express major histocompatibility (MHC) class II molecules, and may play an important role in the presentation of antigen to myelin-specific T cells.However, it has been postulated that astrocytes are unable to act as antigen-presenting cells (APCs) because they would lack the B7 co-stimulatory molecules to activate these T cells. By using double labeling immunofluorescence staining, we demonstrate that reactive astrocytes in chronic active plaques of multiple sclerosis express the co-stimulatory molecules B7-1 and B7-2, and hence have the necessary attributes to act as antigen-presenting cells.

Insulin-like growth factor system regulates oligodendroglial cell behavior : Therapeutic potential in CNS

Amongst the many soluble extracellular factors stimulating intracellular signal transduction pathways and driving cellular processes such as proliferation, differentiation and survival, insulin-like growth factors (IGFs) stand out as indispensable factors for proper oligodendrocyte differentiation and accompanying myelin production. Owing to its potent myelinogenic capacity and its neuroprotective properties, IGFs hold therapeutic potential in demyelinating and neurodengenerative diseases. However, the IGF system is comprised of a complex molecular network involving regulatory binding proteins, proteases, cell surface and extracellular matrix components which orchestrate IGF-specific functions. Thus, the complexity by which these factors are tightly regulated makes a simplistic therapeutic approach towards treating demyelinating conditions unfeasible. In the present review, we address these issues and consider current therapeutic prospects of oligodendrocyte-targeted IGF-based therapies.

Astrocytes in chronic active multiple sclerosis plaques express MHC class II molecules

To initiate the inflammatory cascade leading to demyelination in multiple sclerosis (MS) T cells have to recognize their specific myelin antigen, which needs to be presented in the context of major histocompatibility (MHC) class II molecules expressed on antigen presenting cells. Whether astrocytes can express MHC class II molecules in vivo is a controversial issue. We performed double labeling immunohistochemistry in post-mortem samples from nine patients with MS, three patients with a cerebral infraction and six controls. Astrocytes in controls, in normal appearing white matter in MS, and at the boundary of infarctions were MHC class II negative. In contrast, a subset of astrocytes in active chronic plaques immunostained for MHC class II, indicating potential antigen presenting interactions of astrocytes in MS.

[3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain

By using immunocytochemistry we previously reported the absence of beta(2) adrenergic receptors on astrocytes in multiple sclerosis (MS) white matter. Here, we measured beta(1) and beta(2) adrenergic receptor concentrations in postmortem brain sections of six MS patients and six controls by using quantitative autoradiography with [(3)H]dihydroalprenolol. White matter contained no beta(1) adrenergic receptors. In white matter of controls low levels of beta(2) adrenergic receptors were detected. In agreement with the immunohistochemical study, we were unable to detect beta(2) adrenergic receptors in both normal appearing white matter and astrogliotic plaques in MS. Concentrations of beta(1) and beta(2) adrenergic receptors in cerebral cortex were not different between controls and MS patients.

Astrocytic β2-adrenergic receptors and multiple sclerosis

Abstract Despite intensive research, the cause and a cure of multiple sclerosis (MS) have remained elusive and many aspects of the pathogenesis are not understood. Immunohistochemical experiments have shown that astrocytic β2-adrenergic receptors are lost in MS. Because norepinephrine mediates important supportive and protective actions of astrocytes via activation of these β2-adrenergic receptors, we postulate that this abnormality may play a prominent role in the pathogenesis of MS. First, it may allow astrocytes to act as facultative antigen-presenting cells, thereby initiating T-cell mediated inflammatory responses that lead to the characteristic demyelinated lesions. Second, it may contribute to inflammatory injury by stimulating the production of nitric oxide and proinflammatory cytokines, and reducing glutamate uptake. Third, it may lead to apoptosis of oligodendrocytes by reducing the astrocytic production of trophic factors, including neuregulin, nerve growth factor and brain-derived neurotrophic factor. Fourth, it may impair astrocytic glycogenolysis, which supplies energy to axons, and this may represent a mechanism underlying axonal degeneration that is hold responsible for the progressive chronic disability.

Insulin-Like Growth Factor I Serum Levels Influence Ischemic Stroke Outcome

Background and Purpose— Insulin-like growth factor I (IGF-I) is neuroprotective in animal models of stroke. We investigated whether serum IGF-I levels in patients with acute ischemic stroke influence stroke severity and outcome. Methods— Concentrations of IGF-I and IGF binding protein 3 were measured in serum samples obtained within 6 hours after stroke onset from 255 patients who took part in the placebo arm of the United States and Canadian Lubeluzole in Acute Ischemic Stroke Study. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Multivariate analysis was performed to assess the overall shift in modified Rankin Scale score and changes in the National Institutes of Health Stroke Scale score at 3 months. Survival curves were plotted using the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. Results— After controlling for statistically relevant risk factors, subjects with high IGF-I levels or IGF-I/IGF binding protein 3 ratios had a better neurological and functional outcome at 3 months. Baseline stroke severity was not different between high and low IGF-I groups. In contrast to the low IGF-I group, neurological symptoms gradually improved from Day 3 in the high IGF-I group. Conclusions— Our results suggest that high serum IGF-I levels just after ischemic stroke onset are associated with neurological recovery and a better functional outcome.

The Insulin‐like Growth Factor System in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic disorder of the central nervous system characterized by inflammation, demyelination, and axonal degeneration. Present therapeutic strategies for MS reduce inflammation and its destructive consequences, but are not effective in the progressive phase of the disease. There is a need for neuroprotective and restorative therapies in MS. Insulin-like growth factor-1 (IGF-1) is of considerable interest because it is not only a potent neuroprotective trophic factor but also a survival factor for cells of the oligodendrocyte lineage and possesses a potent myelinogenic capacity. However, the IGF system is complex and includes not only IGF-1 and IGF-2 and their receptors but also modulating IGF-binding proteins (IGFBPs), of which six have been identified. This chapter provides an overview of the role of the IGF system in the pathophysiology of MS, relevant findings in preclinical models, and discusses the possible use of IGF-1 as a therapeutic agent for MS.