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Ceruloplasmin (Cp) concentration and oxidative activity in serum are lowered in Parkinson's disease (PD). In most PD patients, iron increases in the substantia nigra in the midbrain. In PD, the low Cp concentration and activity in serum and the high iron amounts in the substantia nigra appears to be correlated. An hereditary background is common in PD and variations in the Cp gene that have been found in PD are associated with high iron levels in the substantia nigra. Variations in Cp synthesis and in the incorporation of copper into the Cp molecule are essential features of PD. In Alzheimer's disease (AD), the Cp activity in serum is lowered but not the concentration, except in the advanced stages of the disease. Generally, iron is not increased in the AD brain. In the AD brain, iron accumulates in neuritic plaques and in neurofibrillary tangles. There is also increased risk of iron-mediated tissue damage, which may possibly be counteracted by Cp. At the same time, the AD brain is short in copper, which presumably results in the deficient activity of many copper enzymes in the brain, in addition to Cp. Lowered Cp activity in serum most likely stems from lessened incorporation of copper in the Cp molecule and similar incorporation defects might also apply to other copper enzymes in AD.

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Ceruloplasmin, a multi-copper oxidase with four active copper atoms, oxidizes Fe2+ to Fe3+ and concomittantly fully reduces oxygen to water. The oxygenation of iron is a requisite for transferrin transport of iron and keeping noxious Fe2+ low. In the central nervous system (CNS) Cp is mostly localized in end feet of astrocytes surrounding capillaries and attached by a glycosylphosphatidylinositol-anchor. In aceruloplasminaemia, a rare recessive hereditary disease, complete loss of Cp is accompanied by disorders of iron metabolism and lesions in CNS and outside. In PD Cp concentration and oxidative activity in serum are significantly lowered with iron deposits and lesions in substantia nigra and basal ganglia. Changes in Cp-genes might be causative in these disorders. By inducing neuromelanin synthesis Cp may protect neurons in substantia nigra. In AD Cp activity in serum, but not concentration, is significantly lowered. Changes in Cp-genes have not been verified in AD. Total amounts of iron are not increased in AD brains although iron deposits and cortical lesions are numerous. Total copper is significantly lowered in AD brains. This may result in defective synthesis of Cp and other copper enzymes. - In conclusion, the defective Cp activity, associated with iron disorders, is seemingly of importance in PD and also in AD with other copper enzyme defects possibly involved.

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BACKGROUNDS/AIMS: The oxidative activity of ceruloplasmin (CP) in serum has been found to be lowered in patients with Alzheimer's disease (AD). We investigated whether changes in CP were reflected by altered iron parameters in AD patients. METHODS: Iron parameters, and CP concentration, activity and specific activity were determined in the serum of 41 AD patients and controls. RESULTS: CP activity and specific activity were significantly lower in the AD patients. CP concentration and activity were negatively correlated with the ferritin concentration in both groups. CP concentration was positively correlated with age in the control group but not in the patients group. CONCLUSION: The lowered CP activity in the serum of AD patients was not reflected by the iron parameters. As CP concentration only rises with age in the controls, this may indicate failing adaption to age-related alterations in iron metabolism in AD patients.

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This short review describes a series of case-control studies on the concentration and oxidative activity of ceruloplasmin (CP) in serum and the activity of superoxide dismutase (SOD1) in erythrocytes in patients with Alzheimer's disease (AD), Parkinson's disease (PD) and Down's syndrome (DS). The same parameters were re-examined in the PD patients 5 years later. The specific oxidative activity (oxidative activity related to mass) of CP was calculated in PD and DS. In AD and PD the oxidative activity of CP and SOD1 activity was significantly lower in patients than controls. The specific oxidative activity of CP was also significantly lower in PD patients. The difference in all parameters determined was still present 5 years later in PD patients. There was no difference in the concentration or activity of CP in patients with DS and controls. Because of the gene-dose effect (the gene for SOD1 is located on chromosome 21); the SOD1 activity was 50% higher in the patients than the controls. The CP specific oxidative activity and SOD1 activity were found to be significantly lower in the older (>40 years) than the younger DS patients. Whether changes in CP and SOD1 in AD, PD and DS are primary changes or a result of prolonged disease burden needs to be examined.

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At the time of this study, there were five known patients with Wilson disease (WD) in Iceland. The mutation, a 7-bp deletion in exon 7 on chromosome 13 for WD, is only known in Iceland. In twenty healthy Icelandic heterozygotes for WD and their age- and gender-matched controls, copper concentration in plasma, ceruloplasmin (CP) concentration, CP oxidative activity and CP-specific oxidative activity in serum and superoxide dismutase (SOD1) activity in erythrocytes were determined. The same determinations were done on the five WD patients. There was no significant difference in these parameters between the heterozygotes and the controls, although an inclination toward lower CP determinations and higher SOD1 activity in the heterozygotes was noted. As expected the WD patients were low on the copper and CP parameters, but their SOD1 activity was within the upper normal range. In conclusion, the CP parameters and SOD1 activity are within the normal range in Icelandic heterozygotes for WD, although with a trend toward mild dyshomeostasis. This may indicate subclinical copper retention in the heterozygotes, but a bigger study group is needed to confirm this.

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In this follow-up study concentration, oxidative activity and specific oxidative activity of ceruloplasmin (CP) in serum and the activity of superoxide dismutase (SOD1) in erythrocytes were reexamined in 28 of originally 40 patients with Parkinson's disease (PD), and their age- and gender-matched controls. The mean CP and SOD1 parameters were significantly lower in the patients than in the controls. SOD1 activity and age of the patients were inversely correlated. The patients were divided into two subgroups based on their H&Y score i.e. groups II and III (12 patients) versus groups IV and V (16 patients). No significant difference was found in the CP or SOD1 parameters between the subgroups. Patients were also divided into two subgroups based on treatment with levodopa and decarboxylase blocker alone (12 patients) or given additionally a dopamine agonist (15 patients). No significant difference in the parameters was found between these subgroups in relation to intake of dopamine agonists. Results of this study are in agreement with results of the former study 5 years earlier. There is considerable overlap in individual values between patients and controls of the parameters studied. Thus CP and SOD1 have no obvious value for diagnosis or clinical evaluation of PD.

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