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  1. Stefano Olivieri, Antonio Conti, Sandro Iannaccone, Carlo V Cannistraci, Alessandro Campanella, Marco Barbariga, Franca Codazzi, Ilaria Pelizzoni, Giuseppe Magnani, Mariasabina Pesca, Diego Franciotta, Stefano F Cappa and Massimo Alessio.
    Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention.. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(50):18568–77, December 2011.
    Abstract Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.
    URL, DOI BibTeX

    @article{Olivieri2011,
    	abstract = "Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.",
    	author = "Olivieri, Stefano and Conti, Antonio and Iannaccone, Sandro and Cannistraci, Carlo V and Campanella, Alessandro and Barbariga, Marco and Codazzi, Franca and Pelizzoni, Ilaria and Magnani, Giuseppe and Pesca, Mariasabina and Franciotta, Diego and Cappa, Stefano F and Alessio, Massimo",
    	doi = "10.1523/JNEUROSCI.3768-11.2011",
    	issn = "1529-2401",
    	journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
    	keywords = "Aged,Aged, 80 and over,Animals,Astrocytes,Astrocytes: metabolism,Cells, Cultured,Ceruloplasmin,Ceruloplasmin: cerebrospinal fluid,Ceruloplasmin: metabolism,Female,Humans,Iron,Iron: metabolism,Male,Middle Aged,Neurons,Neurons: metabolism,Oxidation-Reduction,Oxidative Stress,Oxidative Stress: physiology,Parkinson Disease,Parkinson Disease: cerebrospinal fluid,Rats,Rats, Sprague-Dawley",
    	month = "dec",
    	number = 50,
    	pages = "18568--77",
    	pmid = 22171055,
    	title = "{Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22171055",
    	volume = 31,
    	year = 2011
    }
    
  2. Johannes Brettschneider, Helga Mogel, Vera Lehmensiek, Tino Ahlert, Sigurd Süssmuth, Albert C Ludolph and Hayrettin Tumani.
    Proteome analysis of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS).. Neurochemical research 33(11):2358–63, November 2008.
    Abstract Cerebrospinal fluid (CSF) is a promising source of biomarkers in amyotrophic lateral sclerosis (ALS). Using the two-dimensional difference in gel electrophoresis (2-D-DIGE), we compared CSF samples from patients with ALS (n = 14) with those from normal controls (n = 14). Protein spots that showed significant differences between patients and controls were selected for further analysis by MALDI-TOF mass spectrometry. For validation of identified spots western blot analysis and ELISA was performed. We identified 2 proteins that were upregulated and 3 proteins that were down-regulated in CSF in ALS. Of these, two proteins (Zn-alpha-2-glycoprotein and ceruloplasmin precursor protein) have not been reported in CSF of patients with ALS so far. In contrast, several other proteins (transferrin, alpha-1-antitrypsin precursor and beta-2-microglobulin) seem to be unspecifically affected in different neurological diseases and may therefore be of limited value as disease-related biochemical markers in ALS. Further evaluation of the candidate proteins identified here is necessary.
    URL, DOI BibTeX

    @article{Brettschneider2008,
    	abstract = "Cerebrospinal fluid (CSF) is a promising source of biomarkers in amyotrophic lateral sclerosis (ALS). Using the two-dimensional difference in gel electrophoresis (2-D-DIGE), we compared CSF samples from patients with ALS (n = 14) with those from normal controls (n = 14). Protein spots that showed significant differences between patients and controls were selected for further analysis by MALDI-TOF mass spectrometry. For validation of identified spots western blot analysis and ELISA was performed. We identified 2 proteins that were upregulated and 3 proteins that were down-regulated in CSF in ALS. Of these, two proteins (Zn-alpha-2-glycoprotein and ceruloplasmin precursor protein) have not been reported in CSF of patients with ALS so far. In contrast, several other proteins (transferrin, alpha-1-antitrypsin precursor and beta-2-microglobulin) seem to be unspecifically affected in different neurological diseases and may therefore be of limited value as disease-related biochemical markers in ALS. Further evaluation of the candidate proteins identified here is necessary.",
    	author = {Brettschneider, Johannes and Mogel, Helga and Lehmensiek, Vera and Ahlert, Tino and S\"{u}ssmuth, Sigurd and Ludolph, Albert C and Tumani, Hayrettin},
    	doi = "10.1007/s11064-008-9742-5",
    	issn = "1573-6903",
    	journal = "Neurochemical research",
    	keywords = "Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Electrophoresis, Gel, Two-Dimensional,Enzyme-Linked Immunosorbent Assay,Female,Humans,Male,Mass Spectrometry,Middle Aged,Proteome",
    	month = "nov",
    	number = 11,
    	pages = "2358--63",
    	pmid = 18481174,
    	title = "{Proteome analysis of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS).}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/18481174",
    	volume = 33,
    	year = 2008
    }
    
  3. Marie-Catherine Boll, Mireya Alcaraz-Zubeldia, Sergio Montes and Camilo Rios.
    Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases.. Neurochemical research 33(9):1717–23, September 2008.
    Abstract The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.
    URL, DOI BibTeX

    @article{Boll2008,
    	abstract = "The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.",
    	author = "Boll, Marie-Catherine and Alcaraz-Zubeldia, Mireya and Montes, Sergio and Rios, Camilo",
    	doi = "10.1007/s11064-008-9610-3",
    	issn = "1573-6903",
    	journal = "Neurochemical research",
    	keywords = "Alzheimer Disease,Alzheimer Disease: cerebrospinal fluid,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Animals,Antioxidants,Antioxidants: metabolism,Biological Markers,Biological Markers: cerebrospinal fluid,Ceruloplasmin,Ceruloplasmin: cerebrospinal fluid,Copper,Copper: cerebrospinal fluid,Humans,Huntington Disease,Huntington Disease: cerebrospinal fluid,Lipid Peroxidation,Neurodegenerative Diseases,Neurodegenerative Diseases: cerebrospinal fluid,Nitric Oxide,Nitric Oxide: cerebrospinal fluid,Parkinson Disease,Parkinson Disease: cerebrospinal fluid,ROC Curve,Superoxide Dismutase,Superoxide Dismutase: cerebrospinal fluid",
    	month = "sep",
    	number = 9,
    	pages = "1717--23",
    	pmid = 18307039,
    	title = "{Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/18307039",
    	volume = 33,
    	year = 2008
    }
    
  4. E F Goodall, M S Haque and K E Morrison.
    Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients.. Journal of neurology 255(11):1652–6, 2008.
    Abstract Iron misregulation promotes oxidative stress, a proposed pathological mechanism in neurodegenerative disease. The aim of this study was to evaluate serum iron metabolism indicators in 60 amyotrophic lateral sclerosis (ALS) patients and 44 age matched controls. Serum ferritin levels were significantly increased in ALS patients compared to controls (p < 0.001), while no differences in the levels of serum iron, transferrin, iron saturation or total iron binding capacity were found. Likewise no differences in C reactive protein (CRP) or caeruloplasmin were detected, suggesting that the elevated ferritin levels in ALS did not merely indicate an acute phase response. The increased ferritin level may reflect a general increase in stored iron or be a consequence of ongoing muscle degeneration.
    URL, DOI BibTeX

    @article{Goodall2008,
    	abstract = "Iron misregulation promotes oxidative stress, a proposed pathological mechanism in neurodegenerative disease. The aim of this study was to evaluate serum iron metabolism indicators in 60 amyotrophic lateral sclerosis (ALS) patients and 44 age matched controls. Serum ferritin levels were significantly increased in ALS patients compared to controls (p < 0.001), while no differences in the levels of serum iron, transferrin, iron saturation or total iron binding capacity were found. Likewise no differences in C reactive protein (CRP) or caeruloplasmin were detected, suggesting that the elevated ferritin levels in ALS did not merely indicate an acute phase response. The increased ferritin level may reflect a general increase in stored iron or be a consequence of ongoing muscle degeneration.",
    	author = "Goodall, E F and Haque, M S and Morrison, K E",
    	doi = "10.1007/s00415-008-0945-0",
    	issn = "0340-5354",
    	journal = "Journal of neurology",
    	keywords = "Aged,Aging,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Analysis of Variance,C-Reactive Protein,C-Reactive Protein: metabolism,Ceruloplasmin,Ceruloplasmin: metabolism,Female,Ferritins,Ferritins: blood,Humans,Iron,Iron: blood,Iron: metabolism,Male,Middle Aged,Normal Distribution,Sex Characteristics",
    	month = "",
    	number = 11,
    	pages = "1652--6",
    	pmid = 18677636,
    	title = "{Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/18677636",
    	volume = 255,
    	year = 2008
    }
    
  5. Antonio Conti, Sandro Iannaccone, Barbara Sferrazza, Lucia De Monte, Stefano Cappa, Diego Franciotta, Stefano Olivieri and Massimo Alessio.
    Differential expression of ceruloplasmin isoforms in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.. Proteomics. Clinical applications 2(12):1628–37, 2008.
    Abstract Amyotrophic lateral sclerosis (ALS) a fatal degenerative disease that selectively affects motor neurons, likely results from a complex interplay among oxidative injury, excitotoxic stimulation, protein aggregation and genetic factors. Ceruloplasmin (Cp) protein is a ferroxidase that oxidizes toxic ferrous iron to its nontoxic ferric form, protecting the central nervous system (CNS) from iron deposition. Cp is thus considered as one of the main systems dedicated to the protection of the CNS from oxidative stress damage. We investigated Cp protein behaviour in the cerebrospinal fluid (CSF) of ALS patients of recent onset. An increased expression of Cp was observed in ALS (n = 16) compared to two control groups (healthy subjects, n = 11 and peripheral neuropathy patients, n = 10). 2-DE analysis revealed a differential expression of Cp isoforms in ALS patients compared to controls. ALS samples showed an increase in the relative abundance of more basic Cp forms, corresponding to the nonsialylated proteins. Despite the increase in protein expression, ferroxidase activity evaluated in the CSF of ALS patients was comparable to that of the controls, indicating a Cp functional impairment. Ceruloplasmin isoforms profile may be proposed as disease feature that could provide insight into the molecular mechanisms of ALS pathogenesis.
    URL, DOI BibTeX

    @article{Conti2008,
    	abstract = "Amyotrophic lateral sclerosis (ALS) a fatal degenerative disease that selectively affects motor neurons, likely results from a complex interplay among oxidative injury, excitotoxic stimulation, protein aggregation and genetic factors. Ceruloplasmin (Cp) protein is a ferroxidase that oxidizes toxic ferrous iron to its nontoxic ferric form, protecting the central nervous system (CNS) from iron deposition. Cp is thus considered as one of the main systems dedicated to the protection of the CNS from oxidative stress damage. We investigated Cp protein behaviour in the cerebrospinal fluid (CSF) of ALS patients of recent onset. An increased expression of Cp was observed in ALS (n = 16) compared to two control groups (healthy subjects, n = 11 and peripheral neuropathy patients, n = 10). 2-DE analysis revealed a differential expression of Cp isoforms in ALS patients compared to controls. ALS samples showed an increase in the relative abundance of more basic Cp forms, corresponding to the nonsialylated proteins. Despite the increase in protein expression, ferroxidase activity evaluated in the CSF of ALS patients was comparable to that of the controls, indicating a Cp functional impairment. Ceruloplasmin isoforms profile may be proposed as disease feature that could provide insight into the molecular mechanisms of ALS pathogenesis.",
    	author = "Conti, Antonio and Iannaccone, Sandro and Sferrazza, Barbara and {De Monte}, Lucia and Cappa, Stefano and Franciotta, Diego and Olivieri, Stefano and Alessio, Massimo",
    	doi = "10.1002/prca.200780081",
    	issn = "1862-8346",
    	journal = "Proteomics. Clinical applications",
    	month = "",
    	number = 12,
    	pages = "1628--37",
    	pmid = 21136813,
    	title = "{Differential expression of ceruloplasmin isoforms in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21136813",
    	volume = 2,
    	year = 2008
    }
    
  6. Irina P Ermilova, Vladimir B Ermilov, Mark Levy, Emily Ho, Cliff Pereira and Joseph S Beckman.
    Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.. Neuroscience letters 379(1):42–6, 2005.
    Abstract Mutations to the copper, zinc superoxide dismutase (SOD) gene are responsible for 2-3% of amyotrophic lateral sclerosis (ALS) cases. These mutations result in the protein having a reduced affinity for zinc. SOD becomes toxic to motor neurons when zinc is missing from its active site. Recently, high dosages of zinc (75 and 375 mg/kg/day) have been paradoxically reported to increase the death of G93A-mutant SOD transgenic mice [G.J. Groeneveld, J. de Leeuw van Weenen, F.L. van Muiswinkel, H. Veldman, J.H. Veldink, J.H. Wokke, P.R. Bar, L.H. van den Berg, Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis, Neurosci. Lett. 352 (2003) 175-178]. In contrast, we have found that moderate supplementation of zinc (approximately 12 mg/kg/day) delayed death in G93A-mutant SOD mice by 11 days compared to mice on a zinc-deficient diet. Supplementing zinc with even 18 mg/kg/day resulted in a more rapid death of some mice, consistent with the results of Groenevelt et al. However, large amounts of zinc competitively inhibit copper absorption, which inhibits the copper-dependent ceruloplasmin, and can cause a lethal anemia. We found that supplementing the 18 mg/kg/day dosage of zinc with 0.3 mg/kg/day of copper prevented the early death from zinc treatment alone. These data support a role for moderate levels of dietary zinc potentially protecting against the toxicity of ALS-associated SOD and the protection does not result from depleting copper.
    URL, DOI BibTeX

    @article{Ermilova2005,
    	abstract = "Mutations to the copper, zinc superoxide dismutase (SOD) gene are responsible for 2-3\% of amyotrophic lateral sclerosis (ALS) cases. These mutations result in the protein having a reduced affinity for zinc. SOD becomes toxic to motor neurons when zinc is missing from its active site. Recently, high dosages of zinc (75 and 375 mg/kg/day) have been paradoxically reported to increase the death of G93A-mutant SOD transgenic mice [G.J. Groeneveld, J. de Leeuw van Weenen, F.L. van Muiswinkel, H. Veldman, J.H. Veldink, J.H. Wokke, P.R. Bar, L.H. van den Berg, Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis, Neurosci. Lett. 352 (2003) 175-178]. In contrast, we have found that moderate supplementation of zinc (approximately 12 mg/kg/day) delayed death in G93A-mutant SOD mice by 11 days compared to mice on a zinc-deficient diet. Supplementing zinc with even 18 mg/kg/day resulted in a more rapid death of some mice, consistent with the results of Groenevelt et al. However, large amounts of zinc competitively inhibit copper absorption, which inhibits the copper-dependent ceruloplasmin, and can cause a lethal anemia. We found that supplementing the 18 mg/kg/day dosage of zinc with 0.3 mg/kg/day of copper prevented the early death from zinc treatment alone. These data support a role for moderate levels of dietary zinc potentially protecting against the toxicity of ALS-associated SOD and the protection does not result from depleting copper.",
    	author = "Ermilova, Irina P and Ermilov, Vladimir B and Levy, Mark and Ho, Emily and Pereira, Cliff and Beckman, Joseph S",
    	doi = "10.1016/j.neulet.2004.12.045",
    	issn = "0304-3940",
    	journal = "Neuroscience letters",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: diet therapy,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: mortality,Analysis of Variance,Animals,Behavior, Animal,Body Weight,Body Weight: drug effects,Dietary Supplements,Disease Models, Animal,Dose-Response Relationship, Drug,Female,Male,Mice,Mice, Inbred BALB C,Mice, Transgenic,Mice, Transgenic: physiology,Reflex,Reflex: physiology,Sex Factors,Superoxide Dismutase,Superoxide Dismutase: genetics,Time Factors,Zinc,Zinc: therapeutic use",
    	month = "",
    	number = 1,
    	pages = "42--6",
    	pmid = 15814196,
    	title = "{Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/15814196",
    	volume = 379,
    	year = 2005
    }
    
  7. Thornorkell Jóhannesson, Jakob Kristinsson and Jón Snæ dal.
    [Neurodegenerative diseases, antioxidative enzymes and copper. A review of experimental research.]. Laeknabladid 89(9):659–671, 2003.
    Abstract Introduction: In almost all degenerative diseases of the brain aggregation of proteins inside neurons or extracellulary, is a common pathological phenomenon regardless of etiology. It is assumed that the biochemical pathways leading to aggregation are more harmful than the aggregations themselves and most likely imply production of free oxygen radicals. This oxidative stress is in the body met by free radical scavengers in the form of specific chemical substances and antioxidative enzymes. It has therefore been postulated that defective free radical defense is a common pathway in most neurodegenerative diseases in humans as well as in other mammals. Material and methods: The concentration of copper and the activity of two antioxidative copper containing enzymes, ceruloplasmin and superoxide dismutase (SOD 1), was analyzed in the blood. A series of case control studies were performed in Alzheimer s disease (AD), Parkinson s disease (PD) and amyotrophic lateral sclerosis (ALS) as well as in Down s syndrome and autism. Furthermore, a study in sheep was conducted in different areas with different risks of infection of scrapie. In that study, in addition, the activity of the selenium-containing enzyme, glutathione peroxidase, was determined as well as the concentration of manganese in blood. Results: The oxidative activity of ceruloplasmin and SOD1 was shown to be significantly lowered in Alzheimer s disease without any signs of copper deficiency. In Parkinson s disease, the oxidative activity of ceruloplasmin was also on the whole shown to be signifcantly lowered, and furthermore, it decreased significantly as well as the SOD1 activity with duration of the disease. In ALS, the means of all of the determinations were shown to be the same, but the equality of variances differed significantly in the patients compared to their controls. In Down s syndrome past the age of 40, when Alzheimer s type changes appear in the brain, the SOD1 activity and the ceruloplasmin specific oxidative activity (activity in relation to concentration) was significantly lowered compared with the younger patients. In autism, a non-degenerative affection of the central nervous system, there was no difference between patients and their controls. In the sheep, the results indicated a relationship between decreased glutathione peroxidase activity, and possibly also SOD1 activity, and increased susceptibility to scrapie infection. No connection was found between ceruloplasmin oxidative activity and susceptibility to scrapie infection. Susceptibility to scrapie infection was apparantly not conntected with low levels of copper or high levels of manganese in blood of the animals. Discussion: The results indicate that the oxidative defenses in four neurodegenerative diseases with different clinical features are defective as the activity of two copper containing antioxidative enzymes, ceruloplasmin and SOD1, was found defective in all of them. In a developmental syndrome (autism), where neither active degenerative changes nor aggregations are found, no such changes in enzyme activity were detected. The results thus support the idea that deranged oxidative defense is a common denominator in the pathogenesis of these diseases. As far as sheep is concerned, the results also indicate, that there is a defect in oxidative defense connected with increased susceptibility to scrapie infection in the form of lowered glutathione peroxidase activity.
    URL BibTeX

    @article{Johannesson2003,
    	abstract = "Introduction: In almost all degenerative diseases of the brain aggregation of proteins inside neurons or extracellulary, is a common pathological phenomenon regardless of etiology. It is assumed that the biochemical pathways leading to aggregation are more harmful than the aggregations themselves and most likely imply production of free oxygen radicals. This oxidative stress is in the body met by free radical scavengers in the form of specific chemical substances and antioxidative enzymes. It has therefore been postulated that defective free radical defense is a common pathway in most neurodegenerative diseases in humans as well as in other mammals. Material and methods: The concentration of copper and the activity of two antioxidative copper containing enzymes, ceruloplasmin and superoxide dismutase (SOD 1), was analyzed in the blood. A series of case control studies were performed in Alzheimer s disease (AD), Parkinson s disease (PD) and amyotrophic lateral sclerosis (ALS) as well as in Down s syndrome and autism. Furthermore, a study in sheep was conducted in different areas with different risks of infection of scrapie. In that study, in addition, the activity of the selenium-containing enzyme, glutathione peroxidase, was determined as well as the concentration of manganese in blood. Results: The oxidative activity of ceruloplasmin and SOD1 was shown to be significantly lowered in Alzheimer s disease without any signs of copper deficiency. In Parkinson s disease, the oxidative activity of ceruloplasmin was also on the whole shown to be signifcantly lowered, and furthermore, it decreased significantly as well as the SOD1 activity with duration of the disease. In ALS, the means of all of the determinations were shown to be the same, but the equality of variances differed significantly in the patients compared to their controls. In Down s syndrome past the age of 40, when Alzheimer s type changes appear in the brain, the SOD1 activity and the ceruloplasmin specific oxidative activity (activity in relation to concentration) was significantly lowered compared with the younger patients. In autism, a non-degenerative affection of the central nervous system, there was no difference between patients and their controls. In the sheep, the results indicated a relationship between decreased glutathione peroxidase activity, and possibly also SOD1 activity, and increased susceptibility to scrapie infection. No connection was found between ceruloplasmin oxidative activity and susceptibility to scrapie infection. Susceptibility to scrapie infection was apparantly not conntected with low levels of copper or high levels of manganese in blood of the animals. Discussion: The results indicate that the oxidative defenses in four neurodegenerative diseases with different clinical features are defective as the activity of two copper containing antioxidative enzymes, ceruloplasmin and SOD1, was found defective in all of them. In a developmental syndrome (autism), where neither active degenerative changes nor aggregations are found, no such changes in enzyme activity were detected. The results thus support the idea that deranged oxidative defense is a common denominator in the pathogenesis of these diseases. As far as sheep is concerned, the results also indicate, that there is a defect in oxidative defense connected with increased susceptibility to scrapie infection in the form of lowered glutathione peroxidase activity.",
    	author = "J\'{o}hannesson, Thornorkell and Kristinsson, Jakob and Sn\ae dal, J\'{o}n",
    	issn = "0023-7213",
    	journal = "Laeknabladid",
    	month = "",
    	number = 9,
    	pages = "659--671",
    	pmid = 16940591,
    	title = "{[Neurodegenerative diseases, antioxidative enzymes and copper. A review of experimental research.]}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16940591",
    	volume = 89,
    	year = 2003
    }
    
  8. Hiroshi Kurisaki, Harumi Yomono, Shigeo Murayama and Akira Hebisawa.
    [Multiple system atrophy with a-/hypo-ceruloplasminemia: distribution of iron in brains of 2 autopsy cases].. Rinshō shinkeigaku = Clinical neurology 42(4):293–8, April 2002.
    Abstract OBJECTIVE: We presented first two cases of multiple system atrophy (MSA) with a-/hypo-ceruloplasminemia (hypo-Cp). To know whether hypo-Cp was a cause of MSA, we investigated distribution of iron in brains. METHODS: Investigating history, neurological sings and symptoms, neuroimagings, and neuropathological findings of the 2 cases, we demonstrate that these 2 cases were typical MSA. Serum ceruloplasmin (Cp) values of two cases were investigated, as well as those of 14 MSA patients diagnosed after the 2 cases. In the 2 cases, we compared distribution of lesions and distribution of iron depositions revealed by Berlin blue stain (iron stain). Further, we compared depositions of iron in substantia nigra, putamen, and dentate nucleus of the 2 cases with those of 4 control MSA, 2 Parkinson's disease (PD), 2 amyotrophic lateral sclerosis (ALS), and 3 controls. RESULTS: Case 1 was 68-year-old man who developed gait disturbance, and had anti-Parkinson disease drugs after diagnosis of PD. Parkinsonism was progressed, and became bed-ridden after 6 years when he died. Neuropathological finding was typical MSA from distribution of lesions, as well as existence of GCIs and NCIs. Case 2 was 61-year-old man who developed parkinsonism. After 9 years, he had tracheostomy, and after 11 years died of renal failure. Neuropathological finding was typical MSA. With an investigation of serum Cp values of clinically diagnosed 14 MSA patients, we found 2 other cases of MSA with hypo-Cp. Iron stain of the 2 brains revealed that iron depositions were found in substantia nigra and putamen, but were not found neither in pontine base, cerebellum, nor inferior olive. Iron depositions were also seen in substantia nigra and putamen of control MSA cases as same degree as MSA with hypo-Cp, but iron depositions were fewer in PD, ALS and controls. CONCLUSION: Clinico-pathological findings of the the 2 cases were those of typical MSA, but were not same as those of previously reported hypo-Cp. Previous reports suggested iron depositions as a cause of brain lesions, but, we concluded that, in the 2 cases, iron depositions were not a direct cause of MSA lesions. However, high incidence of association of hypo-Cp and MSA shown in our study suggests a relation between hypo-Cp and MSA.
    URL BibTeX

    @article{Kurisaki2002,
    	abstract = "OBJECTIVE: We presented first two cases of multiple system atrophy (MSA) with a-/hypo-ceruloplasminemia (hypo-Cp). To know whether hypo-Cp was a cause of MSA, we investigated distribution of iron in brains. METHODS: Investigating history, neurological sings and symptoms, neuroimagings, and neuropathological findings of the 2 cases, we demonstrate that these 2 cases were typical MSA. Serum ceruloplasmin (Cp) values of two cases were investigated, as well as those of 14 MSA patients diagnosed after the 2 cases. In the 2 cases, we compared distribution of lesions and distribution of iron depositions revealed by Berlin blue stain (iron stain). Further, we compared depositions of iron in substantia nigra, putamen, and dentate nucleus of the 2 cases with those of 4 control MSA, 2 Parkinson's disease (PD), 2 amyotrophic lateral sclerosis (ALS), and 3 controls. RESULTS: Case 1 was 68-year-old man who developed gait disturbance, and had anti-Parkinson disease drugs after diagnosis of PD. Parkinsonism was progressed, and became bed-ridden after 6 years when he died. Neuropathological finding was typical MSA from distribution of lesions, as well as existence of GCIs and NCIs. Case 2 was 61-year-old man who developed parkinsonism. After 9 years, he had tracheostomy, and after 11 years died of renal failure. Neuropathological finding was typical MSA. With an investigation of serum Cp values of clinically diagnosed 14 MSA patients, we found 2 other cases of MSA with hypo-Cp. Iron stain of the 2 brains revealed that iron depositions were found in substantia nigra and putamen, but were not found neither in pontine base, cerebellum, nor inferior olive. Iron depositions were also seen in substantia nigra and putamen of control MSA cases as same degree as MSA with hypo-Cp, but iron depositions were fewer in PD, ALS and controls. CONCLUSION: Clinico-pathological findings of the the 2 cases were those of typical MSA, but were not same as those of previously reported hypo-Cp. Previous reports suggested iron depositions as a cause of brain lesions, but, we concluded that, in the 2 cases, iron depositions were not a direct cause of MSA lesions. However, high incidence of association of hypo-Cp and MSA shown in our study suggests a relation between hypo-Cp and MSA.",
    	author = "Kurisaki, Hiroshi and Yomono, Harumi and Murayama, Shigeo and Hebisawa, Akira",
    	issn = "0009-918X",
    	journal = "Rinshō shinkeigaku = Clinical neurology",
    	keywords = "Aged,Ceruloplasmin,Ceruloplasmin: deficiency,Humans,Iron,Iron: metabolism,Male,Middle Aged,Multiple System Atrophy,Multiple System Atrophy: etiology,Putamen,Putamen: metabolism,Substantia Nigra,Substantia Nigra: metabolism",
    	month = "apr",
    	number = 4,
    	pages = "293--8",
    	pmid = 12561083,
    	title = "{[Multiple system atrophy with a-/hypo-ceruloplasminemia: distribution of iron in brains of 2 autopsy cases].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/12561083",
    	volume = 42,
    	year = 2002
    }
    
  9. G Tórsdóttir, J Kristinsson, G Gudmundsson, J Snaedal and T Jóhannesson.
    Copper, ceruloplasmin and superoxide dismutase (SOD) in amyotrophic lateral sclerosis.. Pharmacology & toxicology 87(3):126–30, September 2000.
    Abstract In two previous studies we found copper dyshomeostasis in patients with Alzheimer's disease and in patients with Parkinson's disease. In this study, the levels of copper in plasma, of ceruloplasmin in serum, ceruloplasmin oxidative activity, ceruloplasmin specific oxidative activity (activity related to mass) as well as superoxide dismutase (SOD) activity in erythrocytes have been determined in 14 patients with amyotrophic lateral sclerosis and their healthy age- and gender-matched controls. Three of the patients had a familial form of the disease or were suspected of having it. The mean values of all parameters were found not to differ significantly between the patients and their controls (Student's t-test; P>0.05). By testing the equality of variances (F distribution) we found that the variances of individual results for ceruloplasmin specific oxidative activity and SOD activity differed significantly between the patients group and the controls group (P= 0.021 and P=0.003), but the individual results of these two activities were not correlated (P>0.05). We conclude that disturbances in ceruloplasmin specific oxidative activity and SOD activity could contribute to motor neurone death in amyotrophic lateral sclerosis, and since the two enzyme activities are not correlated it is uncertain which one is more closely related to the pathology of the disease.
    URL BibTeX

    @article{Torsdottir2000,
    	abstract = "In two previous studies we found copper dyshomeostasis in patients with Alzheimer's disease and in patients with Parkinson's disease. In this study, the levels of copper in plasma, of ceruloplasmin in serum, ceruloplasmin oxidative activity, ceruloplasmin specific oxidative activity (activity related to mass) as well as superoxide dismutase (SOD) activity in erythrocytes have been determined in 14 patients with amyotrophic lateral sclerosis and their healthy age- and gender-matched controls. Three of the patients had a familial form of the disease or were suspected of having it. The mean values of all parameters were found not to differ significantly between the patients and their controls (Student's t-test; P>0.05). By testing the equality of variances (F distribution) we found that the variances of individual results for ceruloplasmin specific oxidative activity and SOD activity differed significantly between the patients group and the controls group (P= 0.021 and P=0.003), but the individual results of these two activities were not correlated (P>0.05). We conclude that disturbances in ceruloplasmin specific oxidative activity and SOD activity could contribute to motor neurone death in amyotrophic lateral sclerosis, and since the two enzyme activities are not correlated it is uncertain which one is more closely related to the pathology of the disease.",
    	author = "T\'{o}rsd\'{o}ttir, G and Kristinsson, J and Gudmundsson, G and Snaedal, J and J\'{o}hannesson, T",
    	issn = "0901-9928",
    	journal = "Pharmacology \& toxicology",
    	keywords = "Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: metabolism,Case-Control Studies,Ceruloplasmin,Ceruloplasmin: metabolism,Copper,Copper: blood,Female,Free Radical Scavengers,Free Radical Scavengers: metabolism,Humans,Male,Middle Aged,Superoxide Dismutase,Superoxide Dismutase: metabolism",
    	month = "sep",
    	number = 3,
    	pages = "126--30",
    	pmid = 11068853,
    	title = "{Copper, ceruloplasmin and superoxide dismutase (SOD) in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/11068853",
    	volume = 87,
    	year = 2000
    }
    
  10. D J Waggoner, T B Bartnikas and J D Gitlin.
    The role of copper in neurodegenerative disease.. Neurobiology of disease 6(4):221–30, August 1999.
    Abstract Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.
    URL, DOI BibTeX

    @article{Waggoner1999,
    	abstract = "Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95\% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.",
    	author = "Waggoner, D J and Bartnikas, T B and Gitlin, J D",
    	doi = "10.1006/nbdi.1999.0250",
    	issn = "0969-9961",
    	journal = "Neurobiology of disease",
    	keywords = "Adenosine Triphosphatases,Adenosine Triphosphatases: metabolism,Adenosine Triphosphatases: physiology,Alzheimer Disease,Alzheimer Disease: enzymology,Alzheimer Disease: metabolism,Alzheimer Disease: pathology,Amino Acid Sequence,Amyloid beta-Peptides,Amyloid beta-Peptides: metabolism,Amyloid beta-Peptides: physiology,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Carrier Proteins,Carrier Proteins: metabolism,Carrier Proteins: physiology,Cation Transport Proteins,Ceruloplasmin,Ceruloplasmin: deficiency,Ceruloplasmin: metabolism,Ceruloplasmin: physiology,Copper,Copper: metabolism,Copper: physiology,Hepatolenticular Degeneration,Hepatolenticular Degeneration: enzymology,Hepatolenticular Degeneration: metabolism,Hepatolenticular Degeneration: pathology,Humans,Menkes Kinky Hair Syndrome,Menkes Kinky Hair Syndrome: enzymology,Menkes Kinky Hair Syndrome: metabolism,Menkes Kinky Hair Syndrome: pathology,Mice,Molecular Sequence Data,Neurodegenerative Diseases,Neurodegenerative Diseases: enzymology,Neurodegenerative Diseases: metabolism,Neurodegenerative Diseases: pathology,Prion Diseases,Prion Diseases: metabolism,Prion Diseases: pathology,Prions,Prions: metabolism,Prions: physiology,Recombinant Fusion Proteins,Sequence Homology, Amino Acid",
    	month = "aug",
    	number = 4,
    	pages = "221--30",
    	pmid = 10448050,
    	title = "{The role of copper in neurodegenerative disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/10448050",
    	volume = 6,
    	year = 1999
    }
    
  11. Z M Qian and Q Wang.
    Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders.. Brain research. Brain research reviews 27(3):257–67, 1998.
    Abstract New findings on the role of LfR (lactotransferrin receptor), MTf (melanotransferrin), CP (ceruloplasmin) and DCT1 (Divalent Cation Transporter) in brain iron transport, obtained during the past 3 years, are important advances in the fields of physiology and pathophysiology of brain iron metabolism. According to these findings, disruption in the expression of these proteins in the brain is probably one of the important causes of the altered brain iron metabolism in age-related neurodegenerative diseases, including Parkinson's Disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the involvement of LfR, MTf and DCT1 in iron uptake by and CP in iron egress from different types of brain cells as well as control mechanisms of expression of these proteins in the brain are critical for elucidating the causes of excessive accumulation of iron in the brain and neuronal death in neurodegenerative diseases.
    URL BibTeX

    @article{Qian1998,
    	abstract = "New findings on the role of LfR (lactotransferrin receptor), MTf (melanotransferrin), CP (ceruloplasmin) and DCT1 (Divalent Cation Transporter) in brain iron transport, obtained during the past 3 years, are important advances in the fields of physiology and pathophysiology of brain iron metabolism. According to these findings, disruption in the expression of these proteins in the brain is probably one of the important causes of the altered brain iron metabolism in age-related neurodegenerative diseases, including Parkinson's Disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the involvement of LfR, MTf and DCT1 in iron uptake by and CP in iron egress from different types of brain cells as well as control mechanisms of expression of these proteins in the brain are critical for elucidating the causes of excessive accumulation of iron in the brain and neuronal death in neurodegenerative diseases.",
    	author = "Qian, Z M and Wang, Q",
    	journal = "Brain research. Brain research reviews",
    	keywords = "Animals,Antigens, Neoplasm,Brain,Brain: metabolism,Carrier Proteins,Carrier Proteins: biosynthesis,Ceruloplasmin,Ceruloplasmin: biosynthesis,Humans,Iron,Iron: metabolism,Iron: pharmacokinetics,Melanoma-Specific Antigens,Neoplasm Proteins,Neoplasm Proteins: biosynthesis,Nerve Tissue Proteins,Nerve Tissue Proteins: biosynthesis,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Receptors, Cell Surface,Receptors, Cell Surface: biosynthesis",
    	month = "",
    	number = 3,
    	pages = "257--67",
    	pmid = 9729418,
    	title = "{Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/9729418",
    	volume = 27,
    	year = 1998
    }
    
  12. H A Hartmann and M A Evenson.
    Deficiency of copper can cause neuronal degeneration.. Medical hypotheses 38(1):75–85, 1992.
    Abstract The aim of this article is to emphasize the important role that copper plays in the function of nerve cells. We are reporting preliminary data which suggest that the swelling of axons which we produce in rats by iminodipropionitrile, IDPN, is due to its chelating action on copper, and how conversely supplementation with copper abolishes both symptoms and lesions. The copper values we obtained by atomic absorption spectrophotometry of the spinal cord and brain from the animals fully support this contention. In comparing these results with the diseases that are known to be due to copper deficiency, namely Menkes disease in man, swayback in lambs and several neurological mutant mice, we find not only similar axonal swellings, but also amelioration of symptoms and lesions by early administration of copper. Considering the main forms in which copper is present, we discuss the cuproproteins, i.e. ceruloplasmin and metallothionein, and their role in transport and delivery of copper to various organs. Further, the many cuproenzymes i.e. superoxide dismutase, tryptophan-2,3-dioxygenase, lysine oxidase, cytochrome oxidase, monoamine oxidases, tyrosinase, dopamine-beta-hydroxylase and d-amino levulinate dehydratase are noted for their roles in the nervous system. Finally, we suggest that neuronal copper deficiency should be more fully investigated as a possible etiological factor in the more common neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis, ALS.
    URL BibTeX

    @article{Hartmann1992,
    	abstract = "The aim of this article is to emphasize the important role that copper plays in the function of nerve cells. We are reporting preliminary data which suggest that the swelling of axons which we produce in rats by iminodipropionitrile, IDPN, is due to its chelating action on copper, and how conversely supplementation with copper abolishes both symptoms and lesions. The copper values we obtained by atomic absorption spectrophotometry of the spinal cord and brain from the animals fully support this contention. In comparing these results with the diseases that are known to be due to copper deficiency, namely Menkes disease in man, swayback in lambs and several neurological mutant mice, we find not only similar axonal swellings, but also amelioration of symptoms and lesions by early administration of copper. Considering the main forms in which copper is present, we discuss the cuproproteins, i.e. ceruloplasmin and metallothionein, and their role in transport and delivery of copper to various organs. Further, the many cuproenzymes i.e. superoxide dismutase, tryptophan-2,3-dioxygenase, lysine oxidase, cytochrome oxidase, monoamine oxidases, tyrosinase, dopamine-beta-hydroxylase and d-amino levulinate dehydratase are noted for their roles in the nervous system. Finally, we suggest that neuronal copper deficiency should be more fully investigated as a possible etiological factor in the more common neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis, ALS.",
    	author = "Hartmann, H A and Evenson, M A",
    	issn = "0306-9877",
    	journal = "Medical hypotheses",
    	keywords = "Animals,Brain,Brain: drug effects,Brain: metabolism,Brain: pathology,Chelating Agents,Chelating Agents: pharmacology,Copper,Copper: deficiency,Copper: metabolism,Copper: pharmacology,Disease Models, Animal,Female,Metalloproteins,Metalloproteins: metabolism,Nerve Degeneration,Nerve Degeneration: drug effects,Nitriles,Nitriles: pharmacology,Rats,Spinal Cord,Spinal Cord: drug effects,Spinal Cord: metabolism,Spinal Cord: pathology,Trace Elements,Trace Elements: metabolism",
    	month = "",
    	number = 1,
    	pages = "75--85",
    	pmid = 1614361,
    	title = "{Deficiency of copper can cause neuronal degeneration.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/1614361",
    	volume = 38,
    	year = 1992
    }
    
  13. T I Mzhel'skaia, I A Zavalishin, I A Ivanova-Smolenskaia, E G Larskiĭ, V V Basevich, E D Markova and A S Niiazbekova.
    [Ceruloplasmin activity in the blood during progressive diseases of the central nervous system].. Laboratornoe delo (11):12–6, 1989.
    Abstract Ceruloplasmin (CP) preparations have been used as the reference agents in transition of this protein oxidase activity to blood serum concentrations; the mean concentrations of serum CP varied from 175 to 310 mg/l, depending on the biochemical characteristics of the preparations. Adjustment by the blood serum copper level has proved adequate for clinical studies. CP activity has been found increased in some patients with disseminated sclerosis and lateral amyotrophic sclerosis. CP activity grows with age in normal subjects and in the patients with hereditary extrapyramidal and cerebellar diseases and phenocopies thereof (except hepatocerebral dystrophy). CP activity is higher in women than in men.
    URL BibTeX

    @article{Mzhel'skaia1989,
    	abstract = "Ceruloplasmin (CP) preparations have been used as the reference agents in transition of this protein oxidase activity to blood serum concentrations; the mean concentrations of serum CP varied from 175 to 310 mg/l, depending on the biochemical characteristics of the preparations. Adjustment by the blood serum copper level has proved adequate for clinical studies. CP activity has been found increased in some patients with disseminated sclerosis and lateral amyotrophic sclerosis. CP activity grows with age in normal subjects and in the patients with hereditary extrapyramidal and cerebellar diseases and phenocopies thereof (except hepatocerebral dystrophy). CP activity is higher in women than in men.",
    	author = "Mzhel'skaia, T I and Zavalishin, I A and Ivanova-Smolenskaia, I A and Larskiĭ, E G and Basevich, V V and Markova, E D and Niiazbekova, A S",
    	issn = "0023-6748",
    	journal = "Laboratornoe delo",
    	keywords = "Adolescent,Adult,Aging,Aging: blood,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Ceruloplasmin,Ceruloplasmin: metabolism,Child,Child, Preschool,Female,Humans,Male,Multiple Sclerosis,Multiple Sclerosis: blood,Reference Values,Sex Characteristics",
    	month = "",
    	number = 11,
    	pages = "12--6",
    	pmid = 2481091,
    	title = "{[Ceruloplasmin activity in the blood during progressive diseases of the central nervous system].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/2481091",
    	year = 1989
    }
    
  14. T Domzał and B Radzikowska.
    [Ceruloplasmin and copper in the serum of patients with amyotrophic lateral sclerosis (ALS)].. Neurologia i neurochirurgia polska 17(3):343–6.
    Abstract The serum level of ceruloplasmin and copper were determined in 14 patients with ALS, 9 with Wilson's disease and 10 with other brain diseases. The enzyme level in 8 patients with ALS (57%) was decreased, similarly as in 8 with Wilson's disease (89%), and 2 (20%) in the control group. The mean ceruloplasmin level in the group of patients with Wilson's disease was 50% that in ALS patients. The copper level was decreased in only 1 ALS patient and 1 in the control group, while in patients with Wilson's disease it was low in 8 cases. These changes may be an effect as well as a cause of motor neuron disease.
    URL BibTeX

    @article{Domza,
    	abstract = "The serum level of ceruloplasmin and copper were determined in 14 patients with ALS, 9 with Wilson's disease and 10 with other brain diseases. The enzyme level in 8 patients with ALS (57\%) was decreased, similarly as in 8 with Wilson's disease (89\%), and 2 (20\%) in the control group. The mean ceruloplasmin level in the group of patients with Wilson's disease was 50\% that in ALS patients. The copper level was decreased in only 1 ALS patient and 1 in the control group, while in patients with Wilson's disease it was low in 8 cases. These changes may be an effect as well as a cause of motor neuron disease.",
    	author = "Domzał, T and Radzikowska, B",
    	issn = "0028-3843",
    	journal = "Neurologia i neurochirurgia polska",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Ceruloplasmin,Ceruloplasmin: analysis,Ceruloplasmin: deficiency,Copper,Copper: blood,Humans",
    	number = 3,
    	pages = "343--6",
    	pmid = 6646324,
    	title = "{[Ceruloplasmin and copper in the serum of patients with amyotrophic lateral sclerosis (ALS)].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/6646324",
    	volume = 17
    }