Visitor counter, Heat Map, Conversion tracking, Search Rank

Discussion thread on ALSTDI forum (requires registration on ALSTDI site): http://www.als.net/forum/yaf_postst52433_Blood-Brain-Barrier-BBB.aspx

 

  1. Ethan A Winkler, Jesse D Sengillo, Abhay P Sagare, Zhen Zhao, Qingyi Ma, Edward Zuniga, Yaoming Wang, Zhihui Zhong, John S Sullivan, John H Griffin, Don W Cleveland and Berislav V Zlokovic.
    Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice.. Proceedings of the National Academy of Sciences of the United States of America 111(11):E1035–42, March 2014.
    Abstract Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.
    URL, DOI BibTeX

    @article{Winkler2014a,
    	abstract = "Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.",
    	author = "Winkler, Ethan A and Sengillo, Jesse D and Sagare, Abhay P and Zhao, Zhen and Ma, Qingyi and Zuniga, Edward and Wang, Yaoming and Zhong, Zhihui and Sullivan, John S and Griffin, John H and Cleveland, Don W and Zlokovic, Berislav V",
    	doi = "10.1073/pnas.1401595111",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Winkler et al. - 2014 - Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice(2).pdf:pdf",
    	issn = "1091-6490",
    	journal = "Proceedings of the National Academy of Sciences of the United States of America",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Blood-Nerve Barrier,Blood-Nerve Barrier: pathology,Blood-Nerve Barrier: physiology,Ferrocyanides,Humans,Immunoblotting,In Situ Nick-End Labeling,Male,Mice,Mice, Transgenic,Microscopy, Confocal,Motor Neurons,Motor Neurons: pathology,Motor Neurons: physiology,Nerve Degeneration,Nerve Degeneration: physiopathology,Point Mutation,Point Mutation: genetics,Protein C,Protein C: metabolism,Real-Time Polymerase Chain Reaction,Rotarod Performance Test,Spinal Cord,Spinal Cord: pathology,Spinal Cord: physiology,Superoxide Dismutase,Superoxide Dismutase: genetics,Tight Junction Proteins,Tight Junction Proteins: genetics,Tight Junction Proteins: metabolism,Warfarin",
    	month = "mar",
    	number = 11,
    	pages = "E1035--42",
    	pmid = 24591593,
    	title = "{Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3964055\&tool=pmcentrez\&rendertype=abstract",
    	volume = 111,
    	year = 2014
    }
    
  2. Ethan A Winkler, Jesse D Sengillo, John S Sullivan, Jenny S Henkel, Stanley H Appel and Berislav V Zlokovic.
    Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis.. Acta neuropathologica 125(1):111–20, January 2013.
    Abstract The blood-brain barrier and blood-spinal cord barrier (BSCB) limit the entry of plasma components and erythrocytes into the central nervous system (CNS). Pericytes play a key role in maintaining blood-CNS barriers. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Moreover, transgenic ALS rodents and pericyte-deficient mice develop BSCB disruption with erythrocyte extravasation preceding motor neuron dysfunction. Here, we studied whether BSCB disruption with erythrocyte extravasation and pericyte loss are present in human ALS. We show that 11 of 11 cervical cords from ALS patients, but 0 of 5 non-neurodegenerative disorders controls, possess perivascular deposits of erythrocyte-derived hemoglobin and hemosiderin typically 10-50 $\mu$m in diameter suggestive of erythrocyte extravasation. Immunostaining for CD235a, a specific marker for erythrocytes, confirmed sporadic erythrocyte extravasation in ALS, but not controls. Quantitative analysis revealed a 3.1-fold increase in perivascular hemoglobin deposits in ALS compared to controls showing hemoglobin confined within the vascular lumen, which correlated with 2.5-fold increase in hemosiderin deposits (r = 0.82, p < 0.01). Spinal cord parenchymal accumulation of plasma-derived immunoglobulin G, fibrin and thrombin was demonstrated in ALS, but not controls. Immunostaining for platelet-derived growth factor receptor-$\beta$, a specific marker for CNS pericytes, indicated a 54 % (p < 0.01) reduction in pericyte number in ALS patients compared to controls. Pericyte reduction correlated negatively with the magnitude of BSCB damage as determined by hemoglobin abundance (r = -0.75, p < 0.01). Thus, the BSCB disruption with erythrocyte extravasation and pericyte reductions is present in ALS. Whether similar findings occur in motor cortex and affected brainstem motor nuclei remain to be seen.
    URL, DOI BibTeX

    @article{Winkler2013,
    	abstract = "The blood-brain barrier and blood-spinal cord barrier (BSCB) limit the entry of plasma components and erythrocytes into the central nervous system (CNS). Pericytes play a key role in maintaining blood-CNS barriers. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Moreover, transgenic ALS rodents and pericyte-deficient mice develop BSCB disruption with erythrocyte extravasation preceding motor neuron dysfunction. Here, we studied whether BSCB disruption with erythrocyte extravasation and pericyte loss are present in human ALS. We show that 11 of 11 cervical cords from ALS patients, but 0 of 5 non-neurodegenerative disorders controls, possess perivascular deposits of erythrocyte-derived hemoglobin and hemosiderin typically 10-50 $\mu$m in diameter suggestive of erythrocyte extravasation. Immunostaining for CD235a, a specific marker for erythrocytes, confirmed sporadic erythrocyte extravasation in ALS, but not controls. Quantitative analysis revealed a 3.1-fold increase in perivascular hemoglobin deposits in ALS compared to controls showing hemoglobin confined within the vascular lumen, which correlated with 2.5-fold increase in hemosiderin deposits (r = 0.82, p < 0.01). Spinal cord parenchymal accumulation of plasma-derived immunoglobulin G, fibrin and thrombin was demonstrated in ALS, but not controls. Immunostaining for platelet-derived growth factor receptor-$\beta$, a specific marker for CNS pericytes, indicated a 54 \% (p < 0.01) reduction in pericyte number in ALS patients compared to controls. Pericyte reduction correlated negatively with the magnitude of BSCB damage as determined by hemoglobin abundance (r = -0.75, p < 0.01). Thus, the BSCB disruption with erythrocyte extravasation and pericyte reductions is present in ALS. Whether similar findings occur in motor cortex and affected brainstem motor nuclei remain to be seen.",
    	author = "Winkler, Ethan A and Sengillo, Jesse D and Sullivan, John S and Henkel, Jenny S and Appel, Stanley H and Zlokovic, Berislav V",
    	doi = "10.1007/s00401-012-1039-8",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Winkler et al. - 2013 - Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis.pdf:pdf",
    	issn = "1432-0533",
    	journal = "Acta neuropathologica",
    	keywords = "Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Amyotrophic Lateral Sclerosis: physiopathology,Blood-Brain Barrier,Blood-Brain Barrier: metabolism,Blood-Brain Barrier: physiopathology,Capillary Permeability,Endothelial Cells,Endothelial Cells: metabolism,Female,Humans,Male,Middle Aged,Motor Neurons,Motor Neurons: cytology,Motor Neurons: pathology,Pericytes,Pericytes: cytology,Pericytes: metabolism,Spinal Cord,Spinal Cord: blood supply,Spinal Cord: physiopathology,Tight Junctions,Tight Junctions: metabolism,Tight Junctions: pathology",
    	month = "jan",
    	number = 1,
    	pages = "111--20",
    	pmid = 22941226,
    	title = "{Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3535352\&tool=pmcentrez\&rendertype=abstract",
    	volume = 125,
    	year = 2013
    }
    
  3. Joanna Tarasiuk, Alina Kułakowska, Wiesław Drozdowski, Johannes Kornhuber and Piotr Lewczuk.
    CSF markers in amyotrophic lateral sclerosis.. Journal of neural transmission (Vienna, Austria : 1996) 119(7):747–57, 2012.
    Abstract Amyotrophic lateral sclerosis (ALS, 'Lou Gehrig disease') is the most common, progressive, neurodegenerative, motor neuron disease, causing damage to upper and lower motor neurons, leading to paralysis and death within 3-5 years. Majority of ALS cases are sporadic ALS (SALS) and only 5-10 % of cases are familial ALS (FALS). Pathogenesis of ALS is complicated and still unclear, including genetic, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurofilament accumulation, impaired trophic support, altered glial function, viral infection, immune imbalance and impairment of the blood-brain, blood-spinal cord and blood-cerebrospinal fluid barriers (BBB/BSCB/BCSFB). The CSF analysis is still one of the basic laboratory tools and might reflect pathophysiological alterations in the course of the disease and could provide an insight into disease pathomechanisms. The most important aim of its analysis is evaluation of blood-CSF barrier, which is altered in 46 % of ALS patients. The CSF biomarkers may give insight into ALS pathophysiology and may be useful for early, presymptomatic diagnosis, therapeutic monitoring and the development of new therapeutic strategies. This review summarizes the general concepts of biomarkers in CSF of ALS patients and their potential usefulness in further research.
    URL, DOI BibTeX

    @article{Tarasiuk2012,
    	abstract = "Amyotrophic lateral sclerosis (ALS, 'Lou Gehrig disease') is the most common, progressive, neurodegenerative, motor neuron disease, causing damage to upper and lower motor neurons, leading to paralysis and death within 3-5 years. Majority of ALS cases are sporadic ALS (SALS) and only 5-10 \% of cases are familial ALS (FALS). Pathogenesis of ALS is complicated and still unclear, including genetic, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurofilament accumulation, impaired trophic support, altered glial function, viral infection, immune imbalance and impairment of the blood-brain, blood-spinal cord and blood-cerebrospinal fluid barriers (BBB/BSCB/BCSFB). The CSF analysis is still one of the basic laboratory tools and might reflect pathophysiological alterations in the course of the disease and could provide an insight into disease pathomechanisms. The most important aim of its analysis is evaluation of blood-CSF barrier, which is altered in 46 \% of ALS patients. The CSF biomarkers may give insight into ALS pathophysiology and may be useful for early, presymptomatic diagnosis, therapeutic monitoring and the development of new therapeutic strategies. This review summarizes the general concepts of biomarkers in CSF of ALS patients and their potential usefulness in further research.",
    	author = "Tarasiuk, Joanna and Kułakowska, Alina and Drozdowski, Wiesław and Kornhuber, Johannes and Lewczuk, Piotr",
    	doi = "10.1007/s00702-012-0806-y",
    	issn = "1435-1463",
    	journal = "Journal of neural transmission (Vienna, Austria : 1996)",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Amyotrophic Lateral Sclerosis: pathology,Biological Markers,Biological Markers: cerebrospinal fluid,Blood-Brain Barrier,Blood-Brain Barrier: metabolism,Blood-Brain Barrier: pathology,Humans,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Neurofilament Proteins,Neurofilament Proteins: cerebrospinal fluid,Oxidative Stress,tau Proteins,tau Proteins: cerebrospinal fluid",
    	month = "",
    	number = 7,
    	pages = "747--57",
    	pmid = 22555610,
    	title = "{CSF markers in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22555610",
    	volume = 119,
    	year = 2012
    }
    
  4. Kazunori Miyazaki, Kazuto Masamoto, Nobutoshi Morimoto, Tomoko Kurata, Takahumi Mimoto, Takayuki Obata, Iwao Kanno and Koji Abe.
    Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice.. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 32(3):456–67, 2012.
    Abstract The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow-metabolism coupling is disturbed in motor neuron degeneration of ALS model mice. In vivo capillary imaging showed progressive decrease of capillary diameter, capillary density, and red blood cell speed during the disease course. Spinal blood flow was progressively decreased in the anterior gray matter (GM) from presymptomatic stage to 0.80-fold of wild-type (WT) mice, 0.61 at early-symptomatic, and 0.49 at end stage of the disease. Local spinal glucose utilization (LSGU) was transiently increased to 1.19-fold in anterior GM at presymptomatic stage, which in turn progressively decreased to 0.84 and 0.60 at early-symptomatic and end stage of the disease. The LSGU/SBF ratio representing flow-metabolism uncoupling (FMU) preceded the sequential pathological changes in the spinal cord of ALS mice and was preferentially found in the affected region of ALS. The present study suggests that this early and progressive FMU could profoundly involve in the whole disease process as a vascular factor of ALS pathology, and could also be a potential target for therapeutic intervention of ALS.
    URL, DOI BibTeX

    @article{Miyazaki2012,
    	abstract = "The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow-metabolism coupling is disturbed in motor neuron degeneration of ALS model mice. In vivo capillary imaging showed progressive decrease of capillary diameter, capillary density, and red blood cell speed during the disease course. Spinal blood flow was progressively decreased in the anterior gray matter (GM) from presymptomatic stage to 0.80-fold of wild-type (WT) mice, 0.61 at early-symptomatic, and 0.49 at end stage of the disease. Local spinal glucose utilization (LSGU) was transiently increased to 1.19-fold in anterior GM at presymptomatic stage, which in turn progressively decreased to 0.84 and 0.60 at early-symptomatic and end stage of the disease. The LSGU/SBF ratio representing flow-metabolism uncoupling (FMU) preceded the sequential pathological changes in the spinal cord of ALS mice and was preferentially found in the affected region of ALS. The present study suggests that this early and progressive FMU could profoundly involve in the whole disease process as a vascular factor of ALS pathology, and could also be a potential target for therapeutic intervention of ALS.",
    	author = "Miyazaki, Kazunori and Masamoto, Kazuto and Morimoto, Nobutoshi and Kurata, Tomoko and Mimoto, Takahumi and Obata, Takayuki and Kanno, Iwao and Abe, Koji",
    	doi = "10.1038/jcbfm.2011.155",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Miyazaki et al. - 2012 - Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration.pdf:pdf",
    	issn = "1559-7016",
    	journal = "Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Capillaries,Capillaries: pathology,Disease Models, Animal,Disease Progression,Glucose,Glucose: metabolism,Humans,Mice,Mice, Inbred C57BL,Mice, Transgenic,Microscopy, Fluorescence, Multiphoton,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Nerve Degeneration,Regional Blood Flow,Regional Blood Flow: physiology,Spinal Cord,Spinal Cord: blood supply,Spinal Cord: metabolism,Spinal Cord: pathology,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "",
    	number = 3,
    	pages = "456--67",
    	pmid = 22068226,
    	publisher = "International Society for Cerebral Blood Flow \& Metabolism, Inc.",
    	shorttitle = "J Cereb Blood Flow Metab",
    	title = "{Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice.}",
    	url = "http://dx.doi.org/10.1038/jcbfm.2011.155",
    	volume = 32,
    	year = 2012
    }
    
  5. Svitlana Garbuzova-Davis, Diana G Hernandez-Ontiveros, Maria C O Rodrigues, Edward Haller, Aric Frisina-Deyo, Santhia Mirtyl, Sebastian Sallot, Samuel Saporta, Cesario V Borlongan and Paul R Sanberg.
    Impaired blood-brain/spinal cord barrier in ALS patients.. Brain research 1469:114–28, 2012.
    Abstract Vascular pathology, including blood-brain/spinal cord barrier (BBB/BSCB) alterations, has recently been recognized as a key factor possibly aggravating motor neuron damage, identifying a neurovascular disease signature for ALS. However, BBB/BSCB competence in sporadic ALS (SALS) is still undetermined. In this study, BBB/BSCB integrity in postmortem gray and white matter of medulla and spinal cord tissue from SALS patients and controls was investigated. Major findings include (1) endothelial cell damage and pericyte degeneration, (2) severe intra- and extracellular edema, (3) reduced CD31 and CD105 expressions in endothelium, (4) significant accumulation of perivascular collagen IV, and fibrin deposits (5) significantly increased microvascular density in lumbar spinal cord, (6) IgG microvascular leakage, (7) reduced tight junction and adhesion protein expressions. Microvascular barrier abnormalities determined in gray and white matter of the medulla, cervical, and lumbar spinal cord of SALS patients are novel findings. Pervasive barrier damage discovered in ALS may have implications for disease pathogenesis and progression, as well as for uncovering novel therapeutic targets.
    URL, DOI BibTeX

    @article{Garbuzova-Davis2012,
    	abstract = "Vascular pathology, including blood-brain/spinal cord barrier (BBB/BSCB) alterations, has recently been recognized as a key factor possibly aggravating motor neuron damage, identifying a neurovascular disease signature for ALS. However, BBB/BSCB competence in sporadic ALS (SALS) is still undetermined. In this study, BBB/BSCB integrity in postmortem gray and white matter of medulla and spinal cord tissue from SALS patients and controls was investigated. Major findings include (1) endothelial cell damage and pericyte degeneration, (2) severe intra- and extracellular edema, (3) reduced CD31 and CD105 expressions in endothelium, (4) significant accumulation of perivascular collagen IV, and fibrin deposits (5) significantly increased microvascular density in lumbar spinal cord, (6) IgG microvascular leakage, (7) reduced tight junction and adhesion protein expressions. Microvascular barrier abnormalities determined in gray and white matter of the medulla, cervical, and lumbar spinal cord of SALS patients are novel findings. Pervasive barrier damage discovered in ALS may have implications for disease pathogenesis and progression, as well as for uncovering novel therapeutic targets.",
    	author = "Garbuzova-Davis, Svitlana and Hernandez-Ontiveros, Diana G and Rodrigues, Maria C O and Haller, Edward and Frisina-Deyo, Aric and Mirtyl, Santhia and Sallot, Sebastian and Saporta, Samuel and Borlongan, Cesario V and Sanberg, Paul R",
    	doi = "10.1016/j.brainres.2012.05.056",
    	file = ":C$\backslash$:/Users/riku/Downloads/IMPAIRED\_BLOOD-BRAIN\_BLOOD-SPINAL\_CORD\_BARRIER\_IN\_ALS\_PATIENTS-libre.pdf:pdf",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: ultrasonography,Blood-Brain Barrier,Blood-Brain Barrier: pathology,Blood-Brain Barrier: ultrasonography,Disease Progression,Endothelial Cells,Endothelial Cells: pathology,Endothelial Cells: ultrastructure,Female,Humans,Male,Medulla Oblongata,Medulla Oblongata: pathology,Medulla Oblongata: ultrasonography,Middle Aged,Spinal Cord,Spinal Cord: pathology,Spinal Cord: ultrasonography,Tight Junctions,Tight Junctions: pathology,Tight Junctions: ultrastructure",
    	month = "",
    	pages = "114--28",
    	pmid = 22750125,
    	title = "{Impaired blood-brain/spinal cord barrier in ALS patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22750125",
    	volume = 1469,
    	year = 2012
    }
    
  6. Svitlana Garbuzova-Davis, Maria C O Rodrigues, Diana G Hernandez-Ontiveros, Michael K Louis, Alison E Willing, Cesario V Borlongan and Paul R Sanberg.
    Amyotrophic lateral sclerosis: a neurovascular disease.. Brain research 1398:113–25, 2011.
    Abstract Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated pathogenesis. Compelling evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models, leading to classification of ALS as a neurovascular disease. The present review provides an updated analysis of the normal and impaired BBB/BSCB, focusing on the ALS-altered barrier. Here we describe the roles of cellular components, tight junctions, transport systems, cell interactions, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption, along with recent evidence from experimental and clinical ALS studies. The BBB/BSCB is a promising research area in ALS and this review will reveal some aspects of microvascular pathology in ALS and hopefully provide ideas for the development of new therapeutic strategies.
    URL, DOI BibTeX

    @article{Garbuzova-Davis2011,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated pathogenesis. Compelling evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models, leading to classification of ALS as a neurovascular disease. The present review provides an updated analysis of the normal and impaired BBB/BSCB, focusing on the ALS-altered barrier. Here we describe the roles of cellular components, tight junctions, transport systems, cell interactions, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption, along with recent evidence from experimental and clinical ALS studies. The BBB/BSCB is a promising research area in ALS and this review will reveal some aspects of microvascular pathology in ALS and hopefully provide ideas for the development of new therapeutic strategies.",
    	author = "Garbuzova-Davis, Svitlana and Rodrigues, Maria C O and Hernandez-Ontiveros, Diana G and Louis, Michael K and Willing, Alison E and Borlongan, Cesario V and Sanberg, Paul R",
    	doi = "10.1016/j.brainres.2011.04.049",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Garbuzova-Davis et al. - 2011 - Amyotrophic lateral sclerosis a neurovascular disease.pdf:pdf",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Blood-Brain Barrier,Blood-Brain Barrier: metabolism,Blood-Brain Barrier: pathology,Blood-Brain Barrier: physiopathology,Central Nervous System,Central Nervous System: blood supply,Central Nervous System: metabolism,Central Nervous System: physiopathology,Cerebral Arteries,Cerebral Arteries: metabolism,Cerebral Arteries: physiopathology,Humans",
    	month = "",
    	pages = "113--25",
    	pmid = 21632035,
    	title = "{Amyotrophic lateral sclerosis: a neurovascular disease.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0006899311008705",
    	volume = 1398,
    	year = 2011
    }
    
  7. Roger W Arhart.
    A possible haemodynamic mechanism for amyotrophic lateral sclerosis.. Medical hypotheses 75(4):341–6, 2010.
    Abstract The hypothesis proposed in this article is that a haemodynamic mechanism may cause amyotrophic lateral sclerosis (ALS). The hypothesis is synthesized from three separate streams of medical research: (1) multiple sclerosis (MS) research; (2) ALS research; (3) atherosclerosis research. Each research stream was reviewed as prerequisite for proposing the hypothesis. A vascular mechanism for MS was first advanced in the medical literature 130years ago. Seventy years ago researchers knew that the plaques aligned along a central vein, and the wall of that central vein was damaged and leaky. Twenty-five years ago the refluxing blood mechanism was proposed. Zamboni imaged the veins of MS patients in 2007 and saw stenoses, twistings, and membrane blockages in the jugular, azygous, and vertebral veins, and refluxing venous blood upstream of the constrictions. The refluxing blood damages the blood-brain-barrier (BBB) of the veins. Leakage of blood components into the central nervous system then causes the plaques in the brains of MS people. Zamboni dilated the venous constrictions endovascularly, and the MS symptoms and brain plaques diminished dramatically. ALS research has recently revealed that this disease is started by blood-spinal cord-barrier (BSCB) damage. The ALS mutant mouse shows BSCB damage and down regulation of tight junction proteins Occludin and ZO-1 before motor neuron harm. Samplings of ALS patients' spinal cords show downregulation of mRNA for tight junction proteins compared to controls. Atherosclerosis research provides the mechanism for how the refluxing blood breaks the tight junctions between the endothelial cells of the veins. Atherosclerosis research on blood flow effects shows that normal pulsatile laminar blood flow is necessary for maintenance of the tight junctions between endothelial cells. Abnormal flow conditions, such as turbulent, stopped, or reversed flow, cause downregulation of tight junction proteins Occludin and ZO-1. Blood flow (haemodynamic) effects explain the BBB damage in MS and may explain the BSCB damage in ALS. The hypothesis: ALS is caused by constrictions in veins draining the spinal cord and brain, which cause venous reflux, which downregulates tight junction proteins Occludin and ZO-1, which leads to breaks in the tight junctions between endothelial cells in the veins, which leads to leakage of toxic blood components into CNS tissue. The consequences of the hypothesis are discussed. If a venous constriction can be reached endovascularly it can be dilated, and such dilation may constitute cure of ALS.
    URL, DOI BibTeX

    @article{Arhart2010,
    	abstract = "The hypothesis proposed in this article is that a haemodynamic mechanism may cause amyotrophic lateral sclerosis (ALS). The hypothesis is synthesized from three separate streams of medical research: (1) multiple sclerosis (MS) research; (2) ALS research; (3) atherosclerosis research. Each research stream was reviewed as prerequisite for proposing the hypothesis. A vascular mechanism for MS was first advanced in the medical literature 130years ago. Seventy years ago researchers knew that the plaques aligned along a central vein, and the wall of that central vein was damaged and leaky. Twenty-five years ago the refluxing blood mechanism was proposed. Zamboni imaged the veins of MS patients in 2007 and saw stenoses, twistings, and membrane blockages in the jugular, azygous, and vertebral veins, and refluxing venous blood upstream of the constrictions. The refluxing blood damages the blood-brain-barrier (BBB) of the veins. Leakage of blood components into the central nervous system then causes the plaques in the brains of MS people. Zamboni dilated the venous constrictions endovascularly, and the MS symptoms and brain plaques diminished dramatically. ALS research has recently revealed that this disease is started by blood-spinal cord-barrier (BSCB) damage. The ALS mutant mouse shows BSCB damage and down regulation of tight junction proteins Occludin and ZO-1 before motor neuron harm. Samplings of ALS patients' spinal cords show downregulation of mRNA for tight junction proteins compared to controls. Atherosclerosis research provides the mechanism for how the refluxing blood breaks the tight junctions between the endothelial cells of the veins. Atherosclerosis research on blood flow effects shows that normal pulsatile laminar blood flow is necessary for maintenance of the tight junctions between endothelial cells. Abnormal flow conditions, such as turbulent, stopped, or reversed flow, cause downregulation of tight junction proteins Occludin and ZO-1. Blood flow (haemodynamic) effects explain the BBB damage in MS and may explain the BSCB damage in ALS. The hypothesis: ALS is caused by constrictions in veins draining the spinal cord and brain, which cause venous reflux, which downregulates tight junction proteins Occludin and ZO-1, which leads to breaks in the tight junctions between endothelial cells in the veins, which leads to leakage of toxic blood components into CNS tissue. The consequences of the hypothesis are discussed. If a venous constriction can be reached endovascularly it can be dilated, and such dilation may constitute cure of ALS.",
    	author = "Arhart, Roger W",
    	doi = "10.1016/j.mehy.2010.03.017",
    	issn = "1532-2777",
    	journal = "Medical hypotheses",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: etiology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Atherosclerosis,Atherosclerosis: etiology,Hemodynamics,Hemodynamics: physiology,Humans,Membrane Proteins,Membrane Proteins: metabolism,Mice,Models, Biological,Multiple Sclerosis,Multiple Sclerosis: etiology,Occludin,Phosphoproteins,Phosphoproteins: metabolism,Spinal Cord,Spinal Cord: cytology,Spinal Cord: metabolism,Tight Junctions,Tight Junctions: metabolism,Tight Junctions: physiology,Zonula Occludens-1 Protein",
    	month = "",
    	number = 4,
    	pages = "341--6",
    	pmid = 20400230,
    	publisher = "Elsevier",
    	title = "{A possible haemodynamic mechanism for amyotrophic lateral sclerosis.}",
    	url = "http://www.medical-hypotheses.com/article/S0306-9877(10)00130-1/abstract",
    	volume = 75,
    	year = 2010
    }
    
  8. Atul F Kamath, Anil K Chauhan, Janka Kisucka, Vandana S Dole, Joseph Loscalzo, Diane E Handy and Denisa D Wagner.
    Elevated levels of homocysteine compromise blood-brain barrier integrity in mice.. Blood 107(2):591–3, 2006.
    Abstract Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)-heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.
    URL, DOI BibTeX

    @article{Kamath2006,
    	abstract = "Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)-heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25\% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.",
    	author = "Kamath, Atul F and Chauhan, Anil K and Kisucka, Janka and Dole, Vandana S and Loscalzo, Joseph and Handy, Diane E and Wagner, Denisa D",
    	doi = "10.1182/blood-2005-06-2506",
    	issn = "0006-4971",
    	journal = "Blood",
    	keywords = "Animals,Blood-Brain Barrier,Blood-Brain Barrier: physiology,Brain,Brain: blood supply,Brain: pathology,Cell Adhesion,Cystathionine beta-Synthase,Cystathionine beta-Synthase: genetics,Cystathionine beta-Synthase: physiology,Diet,Evans Blue,Heterozygote,Homocysteine,Homocysteine: blood,Hyperhomocysteinemia,Leukocytes,Leukocytes: metabolism,Mice,Mice, Inbred C57BL,Mice, Knockout,P-Selectin,P-Selectin: metabolism,Up-Regulation",
    	month = "",
    	number = 2,
    	pages = "591--3",
    	pmid = 16189268,
    	title = "{Elevated levels of homocysteine compromise blood-brain barrier integrity in mice.}",
    	url = "http://bloodjournal.hematologylibrary.org/content/107/2/591",
    	volume = 107,
    	year = 2006
    }
    
  9. Char-Huei Lai and Kuo-Hsing Kuo.
    The critical component to establish in vitro BBB model: Pericyte.. Brain research. Brain research reviews 50(2):258–65, 2005.
    Abstract The blood-brain barrier (BBB), a highly regulated membranous barrier of brain capillaries, consists of an intricate network of tight junctions (TJs) that segregate the central nervous system (CNS) from systemic blood circulation and maintain a delicate homeostasis of the CNS environment. While endothelial cells (ECs) of brain capillaries are clearly the principal cellular element of BBB, the formation and regulation of intact BBB structure appear to require the interactions of endothelial cells with other cellular components. Astrocytes, one of the major non-neural cells in the brain, associate closely and interact with capillary endothelial cells during the angiogenesis and BBB development. Current in vitro cellular models for the study of BBB functions often incorporate astrocytes with endothelial cells. However, another foremost cell type, CNS pericyte, which intimately embraces brain capillary endothelium, attracts relatively little attention for its role in developing the in vitro BBB system. This review will analyze the critical functions of pericytes in angiogenesis in various systems and discuss the relevance of these functions in mediating the development, maintenance, and regulation of BBB. The author will also discuss the functional role of actin in both ECs and pericytes, and further elaborate the molecular mechanisms of BBB permeability regulation that involves the transduction pathway-mediated actin remodeling process. Finally, the rationale of incorporating pericytes for establishing a better in vitro BBB model will be emphasized.
    URL, DOI BibTeX

    @article{Lai2005,
    	abstract = "The blood-brain barrier (BBB), a highly regulated membranous barrier of brain capillaries, consists of an intricate network of tight junctions (TJs) that segregate the central nervous system (CNS) from systemic blood circulation and maintain a delicate homeostasis of the CNS environment. While endothelial cells (ECs) of brain capillaries are clearly the principal cellular element of BBB, the formation and regulation of intact BBB structure appear to require the interactions of endothelial cells with other cellular components. Astrocytes, one of the major non-neural cells in the brain, associate closely and interact with capillary endothelial cells during the angiogenesis and BBB development. Current in vitro cellular models for the study of BBB functions often incorporate astrocytes with endothelial cells. However, another foremost cell type, CNS pericyte, which intimately embraces brain capillary endothelium, attracts relatively little attention for its role in developing the in vitro BBB system. This review will analyze the critical functions of pericytes in angiogenesis in various systems and discuss the relevance of these functions in mediating the development, maintenance, and regulation of BBB. The author will also discuss the functional role of actin in both ECs and pericytes, and further elaborate the molecular mechanisms of BBB permeability regulation that involves the transduction pathway-mediated actin remodeling process. Finally, the rationale of incorporating pericytes for establishing a better in vitro BBB model will be emphasized.",
    	author = "Lai, Char-Huei and Kuo, Kuo-Hsing",
    	doi = "10.1016/j.brainresrev.2005.07.004",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lai, Kuo - 2005 - The critical component to establish in vitro BBB model Pericyte.pdf:pdf",
    	issn = 01650173,
    	journal = "Brain research. Brain research reviews",
    	keywords = "Actins,Actins: physiology,Animals,Blood-Brain Barrier,Blood-Brain Barrier: physiology,Capillary Permeability,Capillary Permeability: physiology,Cell Communication,Cytoskeletal Proteins,Cytoskeletal Proteins: physiology,Endothelial Cells,Endothelial Cells: physiology,Humans,Models, Biological,Pericytes,Pericytes: physiology,Signal Transduction,Signal Transduction: physiology",
    	month = "",
    	number = 2,
    	pages = "258--65",
    	pmid = 16199092,
    	title = "{The critical component to establish in vitro BBB model: Pericyte.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S016501730500113X",
    	volume = 50,
    	year = 2005
    }
    
  10. S Haywood and C Vaillant.
    Overexpression of copper transporter CTR1 in the brain barrier of North Ronaldsay sheep: implications for the study of neurodegenerative disease.. Journal of comparative pathology 150(2-3):216–24.
    Abstract Age-related regulatory failure of the brain barrier towards the influx of redox metals such as copper and iron may be associated with the pathological changes that characterize dementias such as Alzheimer's diseases (ADs) and amyotrophic lateral sclerosis (ALS). The integrity of the brain barrier to regulate copper in the brain is maintained by the complex interplay of membrane-located transporters, of which copper transporter 1 (CTR1) exerts a defining role. North Ronaldsay (NR) sheep are a primitive breed that have adapted to a copper-deficient environment by an enhanced uptake of the metal, resulting in copper overload in the liver and brain. This study reports that CTR1 is overexpressed in both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB) of adult NR sheep when compared with a domesticated breed. The excess copper is stored ultimately in astrocytes as non-injurious copper-metallothionein (MT). NR sheep have apparently retained an immature regulatory setting for CTR1 in the BBB, promoting facilitated copper uptake into the brain. This putative failure of maturation of CTR1 allows insight into the regulatory control of brain copper homeostasis, whereby the BBB and BCB act in concert to sequester excess copper and protect neurons from injury. The elevated copper content of the ageing human brain may derive from a dysregulation of CTR1 at the brain barrier, with a return to the default (immature) setting and implications for neurodegenerative disease.
    URL, DOI BibTeX

    @article{Haywood,
    	abstract = "Age-related regulatory failure of the brain barrier towards the influx of redox metals such as copper and iron may be associated with the pathological changes that characterize dementias such as Alzheimer's diseases (ADs) and amyotrophic lateral sclerosis (ALS). The integrity of the brain barrier to regulate copper in the brain is maintained by the complex interplay of membrane-located transporters, of which copper transporter 1 (CTR1) exerts a defining role. North Ronaldsay (NR) sheep are a primitive breed that have adapted to a copper-deficient environment by an enhanced uptake of the metal, resulting in copper overload in the liver and brain. This study reports that CTR1 is overexpressed in both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB) of adult NR sheep when compared with a domesticated breed. The excess copper is stored ultimately in astrocytes as non-injurious copper-metallothionein (MT). NR sheep have apparently retained an immature regulatory setting for CTR1 in the BBB, promoting facilitated copper uptake into the brain. This putative failure of maturation of CTR1 allows insight into the regulatory control of brain copper homeostasis, whereby the BBB and BCB act in concert to sequester excess copper and protect neurons from injury. The elevated copper content of the ageing human brain may derive from a dysregulation of CTR1 at the brain barrier, with a return to the default (immature) setting and implications for neurodegenerative disease.",
    	author = "Haywood, S and Vaillant, C",
    	doi = "10.1016/j.jcpa.2013.09.002",
    	issn = "1532-3129",
    	journal = "Journal of comparative pathology",
    	number = "2-3",
    	pages = "216--24",
    	pmid = 24172593,
    	title = "{Overexpression of copper transporter CTR1 in the brain barrier of North Ronaldsay sheep: implications for the study of neurodegenerative disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24172593",
    	volume = 150
    }
    
 

 

Drug Used Experimentally in Stroke Patients Attenuates ALS in Mice

http://bionews-tx.com/news/2014/04/14/drug-used-experimentally-in-stroke-patients-attenuates-als-in-mice/

A study published by principal investigator Berislav Zlokovic and lead author Ethan Winkler, both from the Center for Neurodegeneration and Regeneration at the University of Southern California in Los Angeles, is among a host of recent research regarding amyotrophic lateral sclerosis. The new study, which was published in PNAS, discovered reasons for the breakdown of the blood-spinal cord barrier (BSCB) that contributes to motor neuron degeneration in a mouse model of ALS.

Under normal conditions, the BSCB prevents toxic molecules in circulating blood from entering the central nervous system. But with ALS, “We know that both people and transgenic rodents afflicted with this disease develop spontaneous breakdown of the blood-spinal cord barrier,” said Dr. Zlokovic in a news release from USC. But according to Dr. Zlokovic, there is a gap in this knowledge because “how these microscopic lesions affect the development of the disease has been unclear. In this study, we show that early motor neuron dysfunction related to the disease in mice is proportional to the degree of damage to the blood-spinal cord barrier and that restoring the integrity of the barrier delays motor neuron degeneration.”