- Email: [email protected]
P3-014 Copper and ceruloplasmin in Alzheimer's disease
Poster Session P3: Diagnosis and Disease Progression - Blood~Plasma~Serum Markers mild AD were randomized to a 24-week course of rosiglitazone (4 mg dally; n = 14) or matched placebo (n = 7). Groups did not differ with respect to age, gender, or MMSE. Plasma samples were collected and frozen at baseline and post-treatment, and subjected to independent sandwich ELISAs for both AI3 1-40 and 1-42. Results: Using repeated-measures ANOVA, there was a significant condition by treatment group interaction, reflecting that levels of both AI3 1-40 and 1-42 decrease over the 6 month trial in the placebotreated group [F(1,19) = 5.24; p < 0.05], whereas the A[3 levels in the rosiglitazone-treated group remained stable. Conclusions: Treatment with the insulin-sensitizing agent rosiglitazone maintained plasma A~ levels in this randomized clinical trial of MCI and AD patients. Although peripheral measurements of A~ currently have limited diagnostic utility, plasma levels of A~ have been shown to decline over the course of the disease (Mayeux et al. 2003). Thus, our results suggest that treatment with rosiglitazone may normalize the progressive decline in plasma A[~ levels typically observed in AD patients. Further study of agents that modulate insulin function will be important in understanding the relationship between insulin and A[3 in AD.
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INCREASING NEOPTERIN PRODUCTION AND TRYPTOPHAN DEGRADATION INDICATE CLINICAL PROGRESSION OF DEMENTIA IN ALZHEIMER'S DISEASE
Imrich Blasko* I, Thomas Bodner 1, Christiana Winkler 2, Andrea Griesmacher 3 Josef Marksteiner 1, Dietmar Fuchs 2.1Dept. of
Psychiatry, Medical University of Innsbruck, Innsbruck, Austria; 2Institute of Medical Chemistry and Biochemistry of Medical University of Innsbruck and Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria; 3Dept. of Medical Diagnostics, Medical University of Innsbruck, Innsbruck, Austria. Contact e-mail: [email protected] Background: The pro-inflammatory reaction of the innate immune system is an established feature of healthy aging and might therefore influence the undergoing pathology and progression of Alzheimer's disease (AD). Neopterin is an immune marker produced by activated monocytes/macrophages and is released upon stimulation with interferon-y (IP-N/). In parallel, IFNy induces indoleamine 2,3-dioxygenase which degrades L-tryptophan to kynurenine. Both, neopterin and kynurenine to tryptophan ratio (kyn/trp), are useful for monitoring of the type I immune response. Objective: In this study, we measured the serum concentrations of neopterin, L-tryptophan and kynurenine in 19 patients with moderate AD. The course of clinical progression was assessed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) cognitive battery. Measurements were performed at baseline and 16 months later. Results: At baseline the means of patients' MMSE and age were 17.3 and 77.9 years. Expectedly, along with the progression of AD the means of CERAD cognitive battery items decreased (mean of MMSE to 13.1). Average neopterin concentrations at baseline were already higher than normal in some patients (8.2 nmol/1) and further increased to 16.1 nmol/1 at month 16 (p < 0.05; paired rank test). Higher neopterin concentrations at baseline correlated with lower L-tryptophan at month 16 (p < 0.01, Spearman rank test). Neither neopterin or L-tryptophan nor kynurenine concentrations correlated with C-reactive protein concentrations. Conclusions: Increased formation of neopterin mad enhanced degradation of tryptophan demonstrate that the type I immune response accelerates as AD progresses and might contribute to the clinical progression of dementia.
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COPPER AND CERULOPLASMIN IN ALZHEIMER'S DISEASE
Rosanna Squitti* 1 Patrizio Pasqualetti 1, Gloria Dal Forno 2, Filomena Moffa 1, Emanuele Cassetta 1, Domenico Lupoi 1 Fabrizio Veruieri 1, Luisa Rossi 3, Mauro Baldassini 1, Paolo M. Rossini 1,4.
t AFaR - Osp. Fatebenefratelli, lsola Tiberina, Rome, Italy," 2Clinica Neurologica, Universit~ Campus Biomedico, Rome, Italy; 3Department of Biology, Tor Vergata University, Rome, Italy; 4IRCCS 'Centro S. Giovanni di Dio-PBF', Brescia, Italy. Contact e-mail: [email protected] Background: Redox transition metals are reactive species likely involved in
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the neurodegeneration of Alzheimer's disease (AD) and beta-Amyloid toxicity may depend on copper-mediated mechanisms. We previously described an increase in serum copper levels specific for AD. Objective: To assess the role of serum copper in relations to its transporting protein ceruloplasmin and other peripheral markers of inflammation in AD. Methods: We studied serum levels of copper, iron, ceruloplasmin, transferrin, as well as total peroxides, antioxidants and other peripheral markers of inflammation in 47 patients with AD, 24 Vascular dementia (VAD) patients and 44 healthy elderly controls. Biochemical variables were related to the patients and controls' clinical status, including neuropsychological, neuroimaging and neurosonological studies. Results: We found that copper (p < 0.001), total peroxides (p = 0.026) and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in AD patients, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in AD, but not in VAD or normal controls, of a larger non ceruloplasmin-bound pool of serum copper. This component is likely bound to smaller micronutrients and aminoacids. Conclusions: We hypothesize the presence in AD of a non ceruloplasmin-bound copper fraction, possibly on an inflammatory basis, that by, entering the exchangeable plasma copper pool may easily pass the blood brain barrier and contribute to AI3:copper brain tissue damage and neurodegeneration.
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NATIVE AND OXIDIZED GLYCOPROTEINS IN ALZHEIMER PLASMA
Hanling Yu* 1, Howard M. Chertkow 1,2 Howard Bergman ~,3, Hyman M. Schipper 1'2. 1Centre for Neurotranslational Research and Bloomfield
Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, PQ, Canada; 2Dept. of Neurology & Neurosurgery and Dept. of Medicine (Geriatrics), McGill University, Montreal, PQ, Canada; 3Dept. of Neurology & Neurosurgery, McGiU University, Montreal, PQ, Canada. Contact e-mail: hanling, yu@ staff mcgill.ca Background: The advent of a biological marker that differentiates early, sporadic Alzheimer disease (AD) from normal aging and other dementing illnesses would represent a significant achievement in the management of this common nenrodegenerative disorder. Several studies have disclosed differences between AD and cognitively-normal elderly controls (NEC) subjects with respect to the concentration, glycosylation or specific oxidation of various brain, CSF and blood proteins. Objective: To determine whether aberrant profiles of native and oxidized plasma glycoproteins distinguish AD patients from NEC. Methods: A proteotoic approach was employed to elucidate possible differential expression of native and oxidized glycoproreins using pooled plasma samples derived from ten patients with sporadic AD and pooled plasma samples from NEC subjects. The plasma samples were fractionated by sequential affinity chromatography on heparin-agarose (HepA) and concanavalin A-agarose (ConA) columns followed by separation on 1D and 2D PAGE gels. Carbonylation (oxidation) of proteins was monitored by in-strip derivatization with DNP and anti-DNP immunoblotting. Results: Nine spots representing gtycoproteins which showed enrichment or high specific oxidation indices in AD HepA-ConA 2D,gels relative to NEC samples were analyzed by MALDI-TOF/MS and identified with high probability (p < 0.001) as isoforms of human transferrin (Tf), hemopexin (Hpx) and ~l-antitrypsin (cd-AT). These glycoproteins were concentrated, respectively, 5-, 6.5- and 107-fold in HepA-ConA eluates derived from AD plasma relative to the NEC samples. Specific oxidation indices of the identified Tf and Hpx isoforms in AD plasma were, respectively, 7.4 and 2.8 relative to NEC. Conclusions: Our findings provide further evidence for systemic derangements in heme/irordredox homeostasis and activation of the acute phase response in sporadic AD. Moreover, the data implicate native or oxidized isoforms of Tf, Hpx and cd-AT as potential peripheral biological markers of this condition.
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INCREASING NEOPTERIN PRODUCTION AND TRYPTOPHAN DEGRADATION INDICATE CLINICAL PROGRESSION OF DEMENTIA IN ALZHEIMER'S DISEASE
Imrich Blasko* I, Thomas Bodner 1, Christiana Winkler 2, Andrea Griesmacher 3 Josef Marksteiner 1, Dietmar Fuchs 2.1Dept. of
Psychiatry, Medical University of Innsbruck, Innsbruck, Austria; 2Institute of Medical Chemistry and Biochemistry of Medical University of Innsbruck and Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria; 3Dept. of Medical Diagnostics, Medical University of Innsbruck, Innsbruck, Austria. Contact e-mail: [email protected] Background: The pro-inflammatory reaction of the innate immune system is an established feature of healthy aging and might therefore influence the undergoing pathology and progression of Alzheimer's disease (AD). Neopterin is an immune marker produced by activated monocytes/macrophages and is released upon stimulation with interferon-y (IP-N/). In parallel, IFNy induces indoleamine 2,3-dioxygenase which degrades L-tryptophan to kynurenine. Both, neopterin and kynurenine to tryptophan ratio (kyn/trp), are useful for monitoring of the type I immune response. Objective: In this study, we measured the serum concentrations of neopterin, L-tryptophan and kynurenine in 19 patients with moderate AD. The course of clinical progression was assessed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) cognitive battery. Measurements were performed at baseline and 16 months later. Results: At baseline the means of patients' MMSE and age were 17.3 and 77.9 years. Expectedly, along with the progression of AD the means of CERAD cognitive battery items decreased (mean of MMSE to 13.1). Average neopterin concentrations at baseline were already higher than normal in some patients (8.2 nmol/1) and further increased to 16.1 nmol/1 at month 16 (p < 0.05; paired rank test). Higher neopterin concentrations at baseline correlated with lower L-tryptophan at month 16 (p < 0.01, Spearman rank test). Neither neopterin or L-tryptophan nor kynurenine concentrations correlated with C-reactive protein concentrations. Conclusions: Increased formation of neopterin mad enhanced degradation of tryptophan demonstrate that the type I immune response accelerates as AD progresses and might contribute to the clinical progression of dementia.
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COPPER AND CERULOPLASMIN IN ALZHEIMER'S DISEASE
Rosanna Squitti* 1 Patrizio Pasqualetti 1, Gloria Dal Forno 2, Filomena Moffa 1, Emanuele Cassetta 1, Domenico Lupoi 1 Fabrizio Veruieri 1, Luisa Rossi 3, Mauro Baldassini 1, Paolo M. Rossini 1,4.
t AFaR - Osp. Fatebenefratelli, lsola Tiberina, Rome, Italy," 2Clinica Neurologica, Universit~ Campus Biomedico, Rome, Italy; 3Department of Biology, Tor Vergata University, Rome, Italy; 4IRCCS 'Centro S. Giovanni di Dio-PBF', Brescia, Italy. Contact e-mail: [email protected] Background: Redox transition metals are reactive species likely involved in
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the neurodegeneration of Alzheimer's disease (AD) and beta-Amyloid toxicity may depend on copper-mediated mechanisms. We previously described an increase in serum copper levels specific for AD. Objective: To assess the role of serum copper in relations to its transporting protein ceruloplasmin and other peripheral markers of inflammation in AD. Methods: We studied serum levels of copper, iron, ceruloplasmin, transferrin, as well as total peroxides, antioxidants and other peripheral markers of inflammation in 47 patients with AD, 24 Vascular dementia (VAD) patients and 44 healthy elderly controls. Biochemical variables were related to the patients and controls' clinical status, including neuropsychological, neuroimaging and neurosonological studies. Results: We found that copper (p < 0.001), total peroxides (p = 0.026) and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in AD patients, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in AD, but not in VAD or normal controls, of a larger non ceruloplasmin-bound pool of serum copper. This component is likely bound to smaller micronutrients and aminoacids. Conclusions: We hypothesize the presence in AD of a non ceruloplasmin-bound copper fraction, possibly on an inflammatory basis, that by, entering the exchangeable plasma copper pool may easily pass the blood brain barrier and contribute to AI3:copper brain tissue damage and neurodegeneration.
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NATIVE AND OXIDIZED GLYCOPROTEINS IN ALZHEIMER PLASMA
Hanling Yu* 1, Howard M. Chertkow 1,2 Howard Bergman ~,3, Hyman M. Schipper 1'2. 1Centre for Neurotranslational Research and Bloomfield
Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, PQ, Canada; 2Dept. of Neurology & Neurosurgery and Dept. of Medicine (Geriatrics), McGill University, Montreal, PQ, Canada; 3Dept. of Neurology & Neurosurgery, McGiU University, Montreal, PQ, Canada. Contact e-mail: hanling, yu@ staff mcgill.ca Background: The advent of a biological marker that differentiates early, sporadic Alzheimer disease (AD) from normal aging and other dementing illnesses would represent a significant achievement in the management of this common nenrodegenerative disorder. Several studies have disclosed differences between AD and cognitively-normal elderly controls (NEC) subjects with respect to the concentration, glycosylation or specific oxidation of various brain, CSF and blood proteins. Objective: To determine whether aberrant profiles of native and oxidized plasma glycoproteins distinguish AD patients from NEC. Methods: A proteotoic approach was employed to elucidate possible differential expression of native and oxidized glycoproreins using pooled plasma samples derived from ten patients with sporadic AD and pooled plasma samples from NEC subjects. The plasma samples were fractionated by sequential affinity chromatography on heparin-agarose (HepA) and concanavalin A-agarose (ConA) columns followed by separation on 1D and 2D PAGE gels. Carbonylation (oxidation) of proteins was monitored by in-strip derivatization with DNP and anti-DNP immunoblotting. Results: Nine spots representing gtycoproteins which showed enrichment or high specific oxidation indices in AD HepA-ConA 2D,gels relative to NEC samples were analyzed by MALDI-TOF/MS and identified with high probability (p < 0.001) as isoforms of human transferrin (Tf), hemopexin (Hpx) and ~l-antitrypsin (cd-AT). These glycoproteins were concentrated, respectively, 5-, 6.5- and 107-fold in HepA-ConA eluates derived from AD plasma relative to the NEC samples. Specific oxidation indices of the identified Tf and Hpx isoforms in AD plasma were, respectively, 7.4 and 2.8 relative to NEC. Conclusions: Our findings provide further evidence for systemic derangements in heme/irordredox homeostasis and activation of the acute phase response in sporadic AD. Moreover, the data implicate native or oxidized isoforms of Tf, Hpx and cd-AT as potential peripheral biological markers of this condition.