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Ann Logan - One of the best experts on this subject based on the ideXlab platform.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus.
Fluids and barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra J SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus
Fluids and Barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus. Methods Accordingly, Communicating Hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging. Results Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels. Conclusions Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in Hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in Communicating Hydrocephalus.
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decorin prevents the development of juvenile Communicating Hydrocephalus
Brain, 2013Co-Authors: Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Anders Daehli Skjolding, M Berry, Ann LoganAbstract:In post-haemorrhagic and other forms of Communicating Hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile Communicating Hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of Hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of Hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic Communicating Hydrocephalus.
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high csf transforming growth factor beta levels after subarachnoid haemorrhage association with chronic Communicating Hydrocephalus
Journal of Neurology Neurosurgery and Psychiatry, 2009Co-Authors: Michael R Douglas, M Berry, Matija Daniel, Catherine Lagord, James Akinwunmi, Andre Jackowski, Caroline Cooper, Ann LoganAbstract:Background: Chronic Communicating Hydrocephalus is a common sequela of subarachnoid haemorrhage and develops when the flow and drainage of CSF are impaired after fibrosis in the subarachnoid space. Released by platelets into the CSF after subarachnoid haemorrhage, transforming growth factor (TGF)β1/β2 are potent fibrogenic agents that may promote post-haemorrhagic fibrosis and chronic Communicating Hydrocephalus. Methods: Temporal changes in total (latent plus active) TGFβ1/β2 CSF levels of post-haemorrhage patients developing acute Hydrocephalus were measured using ELISA to discover if titres were higher in patients that subsequently developed chronic Communicating Hydrocephalus, compared with those that did not. Results: Mean (SD) CSF levels of total TGFβ1 were 97 (42) pg/ml and total TGFβ2 were 395 (39) pg/ml in control patients with (non-haemorrhagic) Hydrocephalus. For days 1–5 post-subarachnoid haemorrhage (dph), levels of 1427 (242) pg/ml and 976 (191) pg/ml were seen for total TGFβ1 and TGFβ2, respectively. Beyond 5 dph, total TGFβ1/β2 levels declined but remained significantly elevated (p Conclusions: Acutely measured levels of TGFβ1/β2 in the CSF of patients with subarachnoid haemorrhage are thus potential prognostic biomarkers for the subsequent development of chronic Communicating Hydrocephalus, indicating likely dependency on CSF shunting.
Zofia Czosnyka - One of the best experts on this subject based on the ideXlab platform.
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ventricular volume load reveals the mechanoelastic impact of Communicating Hydrocephalus on dynamic cerebral autoregulation
PLOS ONE, 2016Co-Authors: Christina Haubrich, Marek Czosnyka, Rolf R Diehl, Peter Smielewski, Zofia CzosnykaAbstract:Several studies have shown that the progression of Communicating Hydrocephalus is associated with diminished cerebral perfusion and microangiopathy. If Communicating Hydrocephalus similarly alters the cerebrospinal fluid circulation and cerebral blood flow, both may be related to intracranial mechanoelastic properties as, for instance, the volume pressure compliance. Twenty-three shunted patients with Communicating Hydrocephalus underwent intraventricular constant-flow infusion with Hartmann’s solution. The monitoring included transcranial Doppler (TCD) flow velocities (FV) in the middle (MCA) and posterior cerebral arteries (PCA), intracranial pressure (ICP), and systemic arterial blood pressure (ABP). The analysis covered cerebral perfusion pressure (CPP), the index of pressure-volume compensatory reserve (RAP), and phase shift angles between Mayer waves (3 to 9 cpm) in ABP and MCA-FV or PCA-FV. Due to intraventricular infusion, the pressure-volume reserve was exhausted (RAP) 0.84+/-0.1 and ICP was increased from baseline 11.5+/-5.6 to plateau levels of 20.7+/-6.4 mmHg. The ratio dRAP/dICP distinguished patients with large 0.1+/-0.01, medium 0.05+/-0.02, and small 0.02+/-0.01 intracranial volume compliances. Both M wave phase shift angles (r = 0.64; p<0.01) and CPP (r = 0.36; p<0.05) displayed a gradual decline with decreasing dRAP/dICP gradients. This study showed that in Communicating Hydrocephalus, CPP and dynamic cerebral autoregulation in particular, depend on the volume-pressure compliance. The results suggested that the alteration of mechanoelastic characteristics contributes to a reduced cerebral perfusion and a loss of autonomy of cerebral blood flow regulation. Results warrant a prospective TCD follow-up to verify whether the alteration of dynamic cerebral autoregulation may indicate a progression of Communicating Hydrocephalus.
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Ventricular Volume Load Reveals the Mechanoelastic Impact of Communicating Hydrocephalus on Dynamic Cerebral Autoregulation
PloS one, 2016Co-Authors: Christina Haubrich, Marek Czosnyka, Rolf R Diehl, Peter Smielewski, Zofia CzosnykaAbstract:Several studies have shown that the progression of Communicating Hydrocephalus is associated with diminished cerebral perfusion and microangiopathy. If Communicating Hydrocephalus similarly alters the cerebrospinal fluid circulation and cerebral blood flow, both may be related to intracranial mechanoelastic properties as, for instance, the volume pressure compliance. Twenty-three shunted patients with Communicating Hydrocephalus underwent intraventricular constant-flow infusion with Hartmann’s solution. The monitoring included transcranial Doppler (TCD) flow velocities (FV) in the middle (MCA) and posterior cerebral arteries (PCA), intracranial pressure (ICP), and systemic arterial blood pressure (ABP). The analysis covered cerebral perfusion pressure (CPP), the index of pressure-volume compensatory reserve (RAP), and phase shift angles between Mayer waves (3 to 9 cpm) in ABP and MCA-FV or PCA-FV. Due to intraventricular infusion, the pressure-volume reserve was exhausted (RAP) 0.84+/-0.1 and ICP was increased from baseline 11.5+/-5.6 to plateau levels of 20.7+/-6.4 mmHg. The ratio dRAP/dICP distinguished patients with large 0.1+/-0.01, medium 0.05+/-0.02, and small 0.02+/-0.01 intracranial volume compliances. Both M wave phase shift angles (r = 0.64; p
Hannah Botfield - One of the best experts on this subject based on the ideXlab platform.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus.
Fluids and barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra J SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus
Fluids and Barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus. Methods Accordingly, Communicating Hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging. Results Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels. Conclusions Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in Hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in Communicating Hydrocephalus.
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decorin prevents the development of juvenile Communicating Hydrocephalus
Brain, 2013Co-Authors: Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Anders Daehli Skjolding, M Berry, Ann LoganAbstract:In post-haemorrhagic and other forms of Communicating Hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile Communicating Hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of Hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of Hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic Communicating Hydrocephalus.
Osama Abdullah - One of the best experts on this subject based on the ideXlab platform.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus.
Fluids and barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra J SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus
Fluids and Barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus. Methods Accordingly, Communicating Hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging. Results Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels. Conclusions Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in Hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in Communicating Hydrocephalus.
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decorin prevents the development of juvenile Communicating Hydrocephalus
Brain, 2013Co-Authors: Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Anders Daehli Skjolding, M Berry, Ann LoganAbstract:In post-haemorrhagic and other forms of Communicating Hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile Communicating Hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of Hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of Hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic Communicating Hydrocephalus.
Ana Maria Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus.
Fluids and barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra J SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus.
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Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile Communicating Hydrocephalus
Fluids and Barriers of the CNS, 2016Co-Authors: Anuriti Aojula, Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Ann Logan, Alexandra SinclairAbstract:Background In an effort to develop novel treatments for Communicating Hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in Communicating Hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in Communicating Hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental Communicating Hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in Communicating Hydrocephalus. Methods Accordingly, Communicating Hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging. Results Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels. Conclusions Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in Hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in Communicating Hydrocephalus.
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decorin prevents the development of juvenile Communicating Hydrocephalus
Brain, 2013Co-Authors: Hannah Botfield, James P. Mcallister, Ana Maria Gonzalez, Osama Abdullah, Anders Daehli Skjolding, M Berry, Ann LoganAbstract:In post-haemorrhagic and other forms of Communicating Hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile Communicating Hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of Hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of Hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic Communicating Hydrocephalus.