Copper Abstracts 2

©

Treatment of Wilson's disease with zinc: XV long-term follow-up studies.
            (Brewer et al., 1998) Download
Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.

The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease.
            (Brewer, 2009) Download
It is a pleasure and an honor to contribute a paper to a special issue of the Journal of the American College of Nutrition honoring Stanley Wallach and Pearl Small. In this brief review I advance the hypothesis that copper toxicity is the major cause of the epidemic of mild cognitive impairment and Alzheimer's disease engulfing our aging population. This epidemic is recent, exploding in the last 50-60 years. The disease was virtually unknown 100 years ago. And it involves only developed countries that use copper plumbing. Something in our environment associated with development is poisoning the minds of our aged. The epidemic is associated with the use of copper plumbing, and the taking of copper in multi-mineral supplements. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier. I review a web of animal and human data that tightens the noose around the hypothesis that copper toxicity is causing the epidemic of Alzeimer's disease and loss of cognition in our aging population.

Issues raised involving the copper hypotheses in the causation of Alzheimer's disease.
            (Brewer, 2011) Download
I present evidence that the epidemic of Alzheimer's disease is a new phenomenon exploding in the latter part of the 20th century in developed countries. I postulate that a major causative factor in the epidemic is the coincident use of copper plumbing, and the ingestion of inorganic copper leaching from the copper plumbing. I present evidence to support this hypothesis and discuss various objections and criticisms that have been raised about the hypothesis, and my responses to these criticisms. I conclude that the hypothesis is well supported by the evidence and deserves serious consideration, because if it is valid, it indentifies a partially preventable cause of Alzheimer's disease.

Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease.
            (Brewer, 2012b) Download
In this special issue about biofactors causing cognitive impairment, we present evidence for and discuss two such biofactors. One is excess copper, causing neuronal toxicity. The other is zinc deficiency, causing neuronal damage. We present evidence that Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years. This leads to the conclusion that something in the developed environment is a major risk factor for AD. We hypothesize that the factor is inorganic copper, leached from the copper plumbing, the use of which coincides with the AD epidemic. We present a web of evidence supporting this hypothesis. Regarding zinc, we have shown that patients with AD are zinc deficient when compared with age-matched controls. Zinc has critical functions in the brain, and lack of zinc can cause neuronal death. A nonblinded study about 20 years ago showed considerable improvement in AD with zinc therapy, and a mouse AD model study also showed significant cognitive benefit from zinc supplementation. In a small blinded study we carried out, post hoc analysis revealed that 6 months of zinc therapy resulted in significant benefit relative to placebo controls in two cognitive measuring systems. These two factors may be linked in that zinc therapy significantly reduced free copper levels. Thus, zinc may act by lowering copper toxicity or by direct benefit on neuronal health, or both.


Copper toxicity in Alzheimer's disease: cognitive loss from ingestion of inorganic copper.
            (Brewer, 2012a) Download
In this review I present the hypothesis that a toxic substance, inorganic copper, ingested from drinking water and vitamin/mineral supplements containing inorganic copper, is at least partially causal of the epidemic of Alzheimer's disease (AD) we are seeing in developed countries. I set the stage for this hypothesis by pointing out that the epidemic is a new disease phenomenon coinciding temporally with the use of copper plumbing in developed countries. The evidence is good that AD was nonexistent or rare in the 1800 s and early 1900 s, and the arguments that elderly people did not exist in those times, or that AD was simply attributed to senility, are refuted. The web of evidence tying ingestion of inorganic copper as a causal factor in AD is strong, and includes AD animal model data where trace amounts of inorganic copper in the drinking water markedly worsened AD, human studies where ingestion of copper supplements, along with a high fat diet, is associated with a marked loss of cognition, human studies showing a markedly higher mortality in elderly women ingesting copper supplements, as well as other data. It is likely that a high fat diet works in conjunction with ingestion of inorganic copper to increase the risk of AD. It is clear that some factor toxic to the brain is present in the environment in developed countries, but not undeveloped countries, and is a major risk factor for AD. I believe that that toxic factor is ingestion of inorganic copper.

Alzheimer's disease causation by copper toxicity and treatment with zinc.
            (Brewer, 2014) Download
Evidence will be presented that the Alzheimer's disease (AD) epidemic is new, the disease being very rare in the 1900s. The incidence is increasing rapidly, but only in developed countries. We postulate that the new emerging environmental factor partially causal of the AD epidemic is ingestion of inorganic copper from drinking water and taking supplement pills, along with a high fat diet. Inorganic copper can be partially directly absorbed and elevate the serum free copper pool. The Squitti group has shown that serum free copper is elevated in AD, correlates with cognition, and predicts cognition loss. Thus, our inorganic copper hypothesis fits well with the Squitti group data. We have also shown that AD patients are zinc deficient compared to age-matched controls. Because zinc is a neuronal protective factor, we postulate that zinc deficiency may also be partially causative of AD. We carried out a small 6 month double blind study of a new zinc formulation and found that in patients age 70 and over, it protected against cognition loss. Zinc therapy also significantly reduced serum free copper in AD patients, so efficacy may come from restoring normal zinc levels, or from lowering serum free copper, or from both.


 

Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer's Disease.
            (Brewer, 2015) Download
It has become clear that copper toxicity is playing a major role in Alzheimer's disease; but why is the brain copper toxicity with cognition loss in Alzheimer's disease so much different clinically than brain copper toxicity in Wilson's disease, which results in a movement disorder? Furthermore, why is the inorganic copper of supplement pills and in drinking water so much more damaging to cognition than the organic copper in food? A recent paper, which shows that almost all food copper is copper-1, that is the copper-2 of foods reverts to the reduced copper-1 form at death or harvest, gives new insight into these questions. The body has an intestinal transport system for copper-1, Ctr1, which channels copper-1 through the liver and into safe channels. Ctr1 cannot absorb copper-2, and some copper-2 bypasses the liver, ends up in the blood quickly, and is toxic to cognition. Humans evolved to handle copper-1 safely, but not copper-2. Alzheimer's is at least in part, a copper-2 toxicity disease, while Wilson's is a general copper overload disease. In this review, we will show that the epidemiology of the Alzheimer's epidemic occurring in developed, but not undeveloped countries, fits with the epidemiology of exposure to copper-2 ingestion leached from copper plumbing and from copper supplement pill ingestion. Increased meat eating in developed countries is also a factor, because it increases copper absorption, and thus over all copper exposure.

Copper-2 Hypothesis for Causation of the Current Alzheimer's Disease Epidemic Together with Dietary Changes That Enhance the Epidemic.
            (Brewer, 2017) Download
Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveal the epidemic is a creature of the last century. That is, the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community. Disappointing because these facts clearly point at an environmental change in the 20th century in developed countries as a major factor in causing the epidemic. Some scientists have discarded the claimed rarity of the disease in the 19th century as incorrect, saying that Alzheimer's disease is a disease of aging and that the increasing lifespan of people accounts for the current high prevalence of the disease, but this cavalier attitude ignores historical data indicating there were many elderly people in the 19th century who were not getting Alzheimer's disease with any significant frequency. In this review, after documenting that the observed assertions about historical and demographic facts are correct, evidence is amassed that the main environmental culprit causing the Alzheimer's epidemic is ingestion of divalent copper or copper-2. The two sources of copper-2 ingestion are drinking water and multimineral supplement pills containing copper. The increase in copper plumbing use in developed countries parallels the increasing prevalence of Alzheimer's disease. It has been shown that enough copper is leached from copper plumbing in most households to cause Alzheimer's disease, using the Alzheimer's disease animal model studies as a guide to toxic levels. It is relatively easy to avoid or greatly diminish copper-2 ingestion by not using copper containing supplement pills and testing drinking water for copper levels. If the copper in water is too high, a simple device can be put on the tap to remove copper. In addition to the copper-2 hypothesis, this review covers dietary changes that enhance the epidemic.

A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health.
            (DiSilvestro et al., 2012) Download
Marginal copper deficiency, which may affect cardiovascular disease risk, is proposed to occur in many adults in Western industrialized countries. The present study tested the hypothesis that in a group of USA adults, increased copper intake would alter readings for blood copper enzymes and markers relevant to cardiovascular disease risk. Healthy middle aged adults with moderately high cholesterol, were given either placebo or copper supplementation (2 mg copper/day as copper glycinate) for 8 weeks. Blood samples were taken before and after the 8 weeks. Copper, but not placebo, raised activities for two copper enzymes, erythrocyte superoxide dismutase 1 and plasma ceruloplasmin. In contrast, five cardiovascular health related plasma parameters were not changed significantly by copper: C-reactive protein, homocysteine, and cholesterol (total, LDL and HDL). However, changes in erythrocyte superoxide dismutase 1 correlated positively with changes in plasma HDL and negatively with plasma homocysteine. Also, copper lowered mean oxidized LDL values, a result that was statistically significant, but inconsistent. In this test population, increased copper intake raised copper enzyme activities, but did not consistently improve the cardiovascular health measures studied.

Copper deficiency myelopathy.
            (Jaiser and Winston, 2010) Download
Acquired copper deficiency has been recognised as a rare cause of anaemia and neutropenia for over half a century. Copper deficiency myelopathy (CDM) was only described within the last decade, and represents a treatable cause of non-compressive myelopathy which closely mimics subacute combined degeneration due to vitamin B12 deficiency. Here, 55 case reports from the literature are reviewed regarding their demographics, aetiology, haematological and biochemical parameters, spinal imaging, treatment and outcome. The pathophysiology of disorders of copper metabolism is discussed. CDM most frequently presented in the fifth and sixth decades and was more common in women (F:M = 3.6:1). Risk factors included previous upper gastrointestinal surgery, zinc overload and malabsorption syndromes, all of which impair copper absorption in the upper gastrointestinal tract. No aetiology was established in 20% of cases. High zinc levels were detected in some cases not considered to have primary zinc overload, and in this situation the contribution of zinc to the copper deficiency state remained unclear. Cytopenias were found in 78%, particularly anaemia, and a myelodysplastic syndrome may have been falsely diagnosed in the past. Spinal MRI was abnormal in 47% and usually showed high T2 signal in the posterior cervical and thoracic cord. In a clinically compatible case, CDM may be suggested by the presence of one or more risk factors and/or cytopenias. Low serum copper and caeruloplasmin levels confirmed the diagnosis and, in contrast to Wilson's disease, urinary copper levels were typically low. Treatment comprised copper supplementation and modification of any risk factors, and led to haematological normalisation and neurological improvement or stabilisation. Since any neurological recovery was partial and case numbers of CDM will continue to rise with the growing use of bariatric gastrointestinal surgery, clinical vigilance will remain the key to minimising neurological sequelae. Recommendations for treatment and prevention are made.

Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial.
            (Kessler et al., 2008a) Download
Disturbed copper (Cu) homeostasis may be associated with the pathological processes in Alzheimer's disease (AD). In the present report, we evaluated the efficacy of oral Cu supplementation in the treatment of AD in a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild AD for 12 months. Sixty-eight subjects were randomized. The treatment was well-tolerated. There were however no significant differences in primary outcome measures (Alzheimer's Disease Assessment Scale, Cognitive subscale, Mini Mental Status Examination) between the verum [Cu-(II)-orotate-dihydrate; 8 mg Cu daily] and the placebo group. Despite a number of findings supporting the hypothesis of environmental Cu modulating AD, our results demonstrate that oral Cu intake has neither a detrimental nor a promoting effect on the progression of AD.

Effect of copper intake on CSF parameters in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial.
            (Kessler et al., 2008b) Download
A plethora of reports suggest that copper (Cu) homeostasis is disturbed in Alzheimer's disease (AD). In the present report we evaluated the efficacy of oral Cu supplementation on CSF biomarkers for AD. In a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial (12 months long) patients with mild AD received either Cu-(II)-orotate-dihydrate (verum group; 8 mg Cu daily) or placebo (placebo group). The primary outcome measures in CSF were Abeta42, Tau and Phospho-Tau. The clinical trial demonstrates that long-term oral intake of 8 mg Cu can be excluded as a risk factor for AD based on CSF biomarker analysis. Cu intake had no effect on the progression of Tau and Phospho-Tau levels in CSF. While Abeta42 levels declined by 30% in the placebo group (P = 0.001), they decreased only by 10% (P = 0.04) in the verum group. Since decreased CSF Abeta42 is a diagnostic marker for AD, this observation may indicate that Cu treatment had a positive effect on a relevant AD biomarker. Using mini-mental state examination (MMSE) and Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) we have previously demonstrated that there are no Cu treatment effects on cognitive performance, however. Finally, CSF Abeta42 levels declined significantly in both groups within 12 months supporting the notion that CSF Abeta42 may be valid not only for diagnostic but also for prognostic purposes in AD.

Copper supplementation improves functional activities of daily living in adults with copper deficiency.
            (Prodan et al., 2011) Download
OBJECTIVE:  Neurologic manifestations of copper deficiency in adults are increasingly recognized. We sought to determine if copper supplementation over a period of 12 months would improve functional activities of daily living (ADLs) in patients with copper deficiency. METHODS:  We studied 15 consecutively diagnosed patients with copper deficiency that received 12 months of copper supplementation. Functional ADLs were evaluated by the Barthel Index (BI), administered at the time of diagnosis and repeated after 12 months of copper supplementation. RESULTS:  BI scores were significantly higher after 12 months of continued supplementation when compared with initial scores [(mean ± SD), 74 ± 11.7 versus 83 ± 13.2, P = 0.007, paired t-test]. A significant inverse linear correlation between the duration of symptoms before treatment and the change in the BI scores was noted (P = 0.005). CONCLUSIONS:  Early initiation and sustained supplementation with copper for at least 12 months may improve functional ADLs in patients with copper deficiency.

Cocoa supplementation for copper deficiency associated with tube feeding nutrition
            (Tokuda et al., 2006) Download
OBJECTIVE: Because of an increasing number of case reports of copper deficiency associated with long-term tube feeding nutrition in Japan, we identified patients with copper deficiency associated with long-term tube feeding and described the prevalence, clinical data and cocoa treatment for these patients. MATERIALS AND METHODS: We conducted a retrospective study to identify patients who were referred from long-term care institutions and had copper deficiency associated with tube feeding. We reviewed all serum copper concentration data during a 6-year period. We also compared admission and post-treatment peripheral blood counts. RESULTS: Among 210 consecutive admissions with nutritional tube feeding from long-term care institutions (N=210), we identified 13 (6.2%) patients with copper deficiency (aged 46-91; 12 women). All patients had anemia, while most had neutropenia. The range of serum copper concentrations of these patients was 0.1-2.4 microg/L (normal; 6.8-12.8 microg/L). Their feeding formulas revealed a low copper content (5 to 12 microg per 100 kcal of each formula). Cocoa powder was used as the treatment. With cocoa supplements, the blood leukocyte count and hemoglobin significantly improved in all patients. Median leukocyte counts were 1,800 /mm(3)at admission and 6,300/mm(3) at follow-up (p=0.001). Median hemoglobin were 7.0 g/dl at admission and 10.3 g/dl at follow-up (p=0.001). Two patients developed transient tachycardia as a possible adverse effect of cocoa. CONCLUSION: We identified many cases with copper deficiency associated with tube feeding in Okinawa, Japan. Cocoa supplement appeared to be a safe and effective treatment. Increasing the copper content of Japanese tube feeding formulas should be considered for its prevention.

 


References

Brewer, GJ, et al. (1998), ‘Treatment of Wilson’s disease with zinc: XV long-term follow-up studies.’, J Lab Clin Med, 132 (4), 264-78. PubMed: 9794697
Brewer, GJ (2009), ‘The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer’s disease.’, J Am Coll Nutr, 28 (3), 238-42. PubMed: 20150596
——— (2011), ‘Issues raised involving the copper hypotheses in the causation of Alzheimer’s disease.’, Int J Alzheimers Dis, 2011 537528. PubMed: 21922048
——— (2012a), ‘Copper toxicity in Alzheimer’s disease: cognitive loss from ingestion of inorganic copper.’, J Trace Elem Med Biol, 26 (2-3), 89-92. PubMed: 22673823
——— (2012b), ‘Copper excess, zinc deficiency, and cognition loss in Alzheimer’s disease.’, Biofactors, 38 (2), 107-13. PubMed: 22438177
——— (2014), ‘Alzheimer’s disease causation by copper toxicity and treatment with zinc.’, Front Aging Neurosci, 6 92. PubMed: 24860501
——— (2015), ‘Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer’s Disease.’, Nutrients, 7 (12), 10053-64. PubMed: 26633489
——— (2017), ‘Copper-2 Hypothesis for Causation of the Current Alzheimer’s Disease Epidemic Together with Dietary Changes That Enhance the Epidemic.’, Chem Res Toxicol, 30 (3), 763-68. PubMed: 28161940
DiSilvestro, RA, et al. (2012), ‘A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health.’, Metabolism, 61 (9), 1242-46. PubMed: 22444781
Jaiser, SR and GP Winston (2010), ‘Copper deficiency myelopathy.’, J Neurol, 257 (6), 869-81. PubMed: 20232210
Kessler, H, et al. (2008a), ‘Intake of copper has no effect on cognition in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial.’, J Neural Transm (Vienna), 115 (8), 1181-87. PubMed: 18587525
Kessler, H, et al. (2008b), ‘Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial.’, J Neural Transm (Vienna), 115 (12), 1651-59. PubMed: 18972062
Prodan, CI, et al. (2011), ‘Copper supplementation improves functional activities of daily living in adults with copper deficiency.’, J Clin Neuromuscul Dis, 12 (3), 122-28. PubMed: 21321490
Tokuda, Y., et al. (2006), ‘Cocoa supplementation for copper deficiency associated with tube feeding nutrition’, Intern Med, 45 (19), 1079-85. PubMed: 17077570