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ARTICLES: R. Squitti, D. Lupoi, P. Pasqualetti, G. Dal Forno, F. Vernieri, P. Chiovenda, L. Rossi, M. Cortesi, E. Cassetta, and P. M. Rossini Elevation of serum copper levels in Alzheimer’s disease Neurology 2002; 59: 1153-1161 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

Rosanna Squitti, Domenico Lupoi, Patrizio Pasqualetti, Gloria Dal Fomo, Fabrizio Vemieri, Paola Chiovenda, Luisa Rossi, Maurizio Cortesi, Emanuele Cassetta, and Paolo Maria Rossini   (22 January 2003)

Elevation of serum copper levels in Alzheimer’s disease

Steven Brenner   (22 January 2003)

Reply to Letter to the Editor 22 January 2003
Rosanna Squitti AFaR-Osp. Fatebenefratelli Rome Italy, Domenico Lupoi, Patrizio Pasqualetti, Gloria Dal Fomo, Fabrizio Vemieri, Paola Chiovenda, Luisa Rossi, Maurizio Cortesi, Emanuele Cassetta, and Paolo Maria Rossini Send Correspondence to journal: Re: Reply to Letter to the Editor squitti{at}iess.rm.cnr.it Rosanna Squitti, et al.	Thank you for giving us the opportunity to reply to the interesting issues raised by Dr S. Brenner. Variations in serum copper concentrations occur because of age, sex, hormone state, diet and geographical factors, [2] therefore each laboratory should establish its own normal range, particularly for the elderly population. Healthy elderly individuals studied by our laboratory had copper levels within the 10-16 mmol/l range. On this basis we could say that copper levels in AD patients were different from controls. Whether this is “pathological” is yet to be proven. Moreover, we feel that the term “pathological” should be considered in the context of a particular condition and not in general, especially taking into consideration that serum copper levels in Wilson’s disease patients, a degenerative condition where copper metabolism abnormalities are well established, are within the normal reference range. Copper levels in the study by Snaedal et al., [1] were determined on plasma, not on serum, like in our investigation, and we think this does not allow to make a direct comparison. Molina et al. [3] and Ozcankaya et al. [4] found no differences in serum copper levels between AD and controls, but Gonzales et al. [5] obtained results similar to ours. We feel therefore that the debate is still open, and that further investigations need to take into consideration regional variations of diet, life style or genetic make up. Ceruloplasmin and its relationship to copper levels, as Dr. Brenner suggests, do appear to be key issues. With regards to this, we have indeed estimated peripheral ceruloplasmin levels in our AD population. [6] We found that ceruloplasmin and copper levels were 16% and 36% significantly higher in AD patients than in controls (manuscript in preparation). These results support the notion of an impaired ceruloplasmin-copper metabolism in AD, as well as the possible the presence of an additional component of unbound copper (approximately 20% extra). The suggestion made by Brenner that carnosine mediated protection from toxic trace metals may be specifically impaired in AD, as suggested by the early olfactory changes seen in these patients, could indeed relate well to an unbound copper pool, as supported by our results. The exchangeable copper pool, as known from Wilson’s disease studies, is carried by aminoacids or small peptides and it can easily pass the blood brain barrier, making this trace metal directly available for toxic reactions in carnosine deficient brain tissue. References: 1.Snaedal J, Kristinsson J, Gunnarsdottier S, et. Al. Copper Ceruloplasmin and superoxide dismutae in patients with Alzheimer's disease, a case-control study. Dement Geriatr Cogn Disord 1998;9:239-242. 2. Johnson PE, Milne DB, Ikken GI. Effects of age and sex on copper absorption, biological half-life, and status in humans. Am J Clin Nutr 1992;56:917-925. 3. Molina JA, Jimenez-Jimenez FJ, Aguilar MV, et al. Cerebrospinal fluid levels of transition metals in patients with Alzheimer’s disease. J Neural Transm 1998;105:479-488. 4. Ozcankaya R, Delibas N. Malondialdehyde, superoxide dismutase, melatonin, iron, copper and zinc blood concentrations in patients with Alzheimer Disease: Cross-Sectional study. Croat Med J 2002;43:28-32. 5.Gonzàlez C, Martin T, Cacho J, et al. Serum zinc, copper, insulin, and lipids in Alzheimer’s disease epsilon 4 apolipoprotein E allele carriers. Eur J Clin Invest 1999;29:637-642. 6.Squitti R, Cesaretti S, Pasqualetti P, et al. Ceruloplasmin implication in copper mediated toxicity of Alzheimer’s disease. The 8th International Conference of Alzheimer’s disease and Related Disorders 1458; 20-25 July 2002 Stockholm, Sweden. Abstract.
Elevation of serum copper levels in Alzheimer’s disease 22 January 2003
Steven Brenner St. Louis VA Medical Center and St. Louis University Medical Center Send Correspondence to journal: Re: Elevation of serum copper levels in Alzheimer’s disease Sbren20979{at}aol.com Steven Brenner	I read with interest the article referring to elevated serum copper levels in AD [1]. The copper levels referred to in the article as being above (16 umol/L) are within the usual reference range of 10-22 umol/L at laboratories performing analyses of serum copper levels. [2] It appears there are higher concentrations of copper in patients with AD than in healthy controls, however, the levels referred to are still within the usual reference range for copper levels in plasma. Apparently total copper levels including ceruloplasmin bound levels were being referred to. A prior study by Snaedal et al. [3] noted copper and ceruloplasmin concentration in plasma in AD patients were not significantly different from healthy age and gender-matched controls, however ceruloplasmin oxidative activity in plasma of Alzheimer's patients was greatly reduced when compared to that of age and gender-matched controls. Ceruloplasmin determination in plasma would enable determining if there is excessive unbound copper in the plasma. If normal copper levels are toxic to the nervous system, contributing to development of AD, then probably endogenous substances, which usually protect the nervous system, are either less active or decreased with aging. Carnosine has been noted to be able to rescue neurons from copper and zinc mediated neurotoxicity [4] and is expressed in glial cells in the brain and neuronal pathways of the visual and olfactory systems. Since the olfactory system deteriorates in AD with impaired smell [5], carnosine levels are probably deficient in the nervous system with subsequent decreased modulation of copper toxicity. References: 1. Squitti, R Lupoi D, Pasqualetti P et. Al. Elevation of serum copper levels in Alzheimer's disease. Neurology 2002;59:1153-1161. 2. Trace Element and Micronutrient Unit (Scotland's specialized laboratory for trace elements and vitamins in health and disease. Sample Requirements and Reference Values, http://www/griteu/demon.co.uk/Copper.htm 3. Snaedal J, Kristinsson J, Gunnarsdottier S, et. Al. Copper Ceruloplasmin and superoxide dismutae in patients with Alzheimer's disease, a case-control study. Dement Geriatr Cogn Disord 1998;9:239-242. 4. Horning MS, Blakemomre LJ, Trombley PQ. Endogenous mechanisms of neuroprotection: role of zinc, copper and carnosine. Brain Res 2000;852:56 -61. 5. Bacon AW, Bondi MW, Salmon DP, Murphy C. Very early changes in olfactory functioning due to Alzheimer's disease and the role of apolipoprotein E in olfaction. Ann NY Acad Sci 1998;855:723-731.