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To evaluate whether zinc levels in serum, plasma, and cerebrospinal fluid are altered in Alzheimer's disease (AD), we performed meta-analyses of 27 studies on the topic published from 1983 to 2014. The subjects' sample obtained by merging studies was a pooled total of 777 AD subjects and 1,728 controls for serum zinc studies, 287 AD subjects and 166 controls for plasma zinc, and of 292 AD subjects and 179 controls for CSF zinc. The main result of this meta-analysis is the very high heterogeneity among the studies either in demographic terms or in methodological approaches. Although we considered these effects in our analyses, the heterogeneity persisted and it has to be taken into account in the interpretation of the results. Our meta-analysis indicated that serum zinc appears significantly decreased in AD patients compared with healthy controls, and this result is confirmed when serum and plasma studies were analyzed together. If we considered the age-matched studies, the meta-analysis carried out on only six studies showed no significant difference in zinc levels between AD and healthy controls (SMD =-0.55, 95% CI (-1.18; 0.09); p = 0.094; I2 = 91%). In the light of these findings, we speculated about the possibility that the decreases observed could indicate a possible dietary zinc deficiency and we suggested that the possible involvement of zinc alterations in AD may have an interplay with copper metabolism.

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., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

To evaluate zinc status in Alzheimer's disease and Parkinson's disease, 29 patients with Alzheimer's disease, 30 patients with Parkinson's disease, and 29 age- and sex-matched controls were studied. All patients and controls were older than age 50, and all zinc and copper supplements were prohibited beginning 30 days prior to study. Patients were diagnosed by standard criteria. Blood zinc and urine zinc were measured. Urine zinc was measured in a casual specimen, standardized for dilution by reference to creatinine content. Results showed a significantly lower blood zinc in patients with Alzheimer's and patients with Parkinson's than in controls. Urine zinc excretion, normalized to urine creatinine excretion, was not significantly different in either patient group compared to controls. These patients are probably zinc deficient because of nutritional inadequacy.

Neurodegeneration of the central and peripheral nervous system associated with hypocupremia and hyperzincinemia has been widely recognized but the origin of high zinc remained unknown. Denture cream has been recently suggested as one possible source of zinc, but the frequency with which denture fixative alone accounts for this syndrome is unknown. We analyzed the origin of excessive zinc in eleven patients with a progressive myelopolyneuropathy and unexplained hypocupremia with hyperzincinemia. These patients had a detailed clinical assessment, determination of zinc and copper levels, and analyzed use of denture cream with the estimates of daily zinc exposure. We identified denture cream as a source of excessive zinc in 100% patients in our cohort. They all had a history of ill-fitting dentures requiring large amounts of denture cream, resulting in significant zinc exposure. Their copper and zinc normalized after stopping denture cream, further confirming that this is the source of high zinc. Inappropriate use of denture cream appears to be the sole source of excessive zinc in these patients.

Wilson's disease, an autosomal recessive disease of copper accumulation and copper toxicity primarily in the liver and brain, has been the engine that has driven the development of anticopper drugs. Here we first briefly review Wilson's disease, then review the four anticopper drugs used to treat Wilson's disease. We then discuss the results of therapy with anticopper drugs in Wilson's disease, with special emphasis on the newer and better drugs, zinc and tetrathiomolybdate. We then discuss new areas of anticopper therapy, lowering copper availability with tetrathiomolybdate as a therapy in fibrotic, inflammatory, and autoimmune disorders. Many of the cytokines which promote these disorders are copper dependent, and lowering copper availability lessens the activity of these cytokines, favorably influencing a variety of disease processes. Copper in the blood can be thought of as in two pools. One pool is covalently bound in ceruloplasmin, a protein containing six coppers, synthesized by the liver and secreted into the blood. Ceruloplasmin copper accounts for almost 85 to 90% of the blood copper in normal people. This copper is tightly bound and not readily available for cellular uptake and copper toxicity. The other 10-15% of copper is more loosely bound to albumin and other small molecules in the blood, and is readily and freely available to cells and available to cause copper toxicity, if this pool of copper is increased. We call this latter pool of copper "free" copper because of its more ready availability. However, it should be understood that it is not completely free, always being bound to albumin and other molecules. It is this pool of free copper that is greatly expanded in untreated Wilson's patients undergoing copper toxicity.

Tetrathiomolybdate (TM), presumably by lowering copper levels and availability, has shown excellent efficacy in animal models of cancer and models of injury that produce fibrotic or inflammatory damage in lung, heart, and liver. Trials in human patients are underway. If the efficacy of TM is indeed through lowering copper levels, other anticopper drugs should be equally efficacious. Zinc is an anticopper drug, with proven efficacy in Wilson's disease, a disease of copper toxicity. In this study, the efficacy of zinc is compared with TM on a mouse tumor model and on the doxorubicin model of heart damage, and it is hypothesized that when copper availability is lowered to an equivalent extent, the 2 drugs would show equivalent efficacy. No effect is found of zinc on inhibiting growth of a tumor that is markedly inhibited by TM, and zinc is found to be less effective than TM in inhibiting cardiac damage from doxorubicin. This study shows that TM's mechanism of action in protecting against doxorubicin toxicity is because of its anticopper effects, as copper supplementation eliminated the protective effect of TM. It is also hypothesized that the differences between TM and zinc may be caused by TM's mechanism of action in which it binds copper already in the body, whereas zinc does not.

The treatment of Wilson's disease has changed considerably in recent times, from the use of penicillamine (Cuprimine, Merck) for all stages and types of disease, to the use of three other anticopper drugs at appropriate times for appropriate patients. Each type and stage of the disease can be considered as a therapeutic target, for which specialised therapy is appropriate. This paper systematically reviews the various types and stages of Wilson's disease presentation, and provides opinion on the appropriate therapy for each. For patients presenting with neurological disease, the use of tetrathiomolybdate is optimum; for patients presenting with mild-to-moderate hepatic failure, a combination of trientine (Syprine, Merck) and zinc is recommended, whereas liver transplantation is necessary for those with severe failure; zinc therapy alone or trientine alone as second choice is recommended for patients presenting with hepatitis or cirrhosis without liver failure, for maintenance therapy, for treatment of presymptomatic patients and for treatment of paediatric and pregnant patients.

We have treated 9 patients who presented with hepatic decompensation resulting from Wilson's disease with a combination of trientine and zinc, generally for at least 4 months, followed by transition to zinc maintenance therapy. All of these patients had hypoalbuminemia, all but 1 had hyperbilirubinemia, and 7 had ascites. All of these patients would have been candidates for liver transplantation on the basis of their initial Child-Turcotte-Pugh (CTP) scores. The minimal listing criteria for transplant candidates is a score greater than 7. Eight of the 9 patients had demonstrated a CTP score of 10 or higher. The other scoring system that has been used in Wilson's disease to determine need for transplantation is the prognostic index of Nazer, in which a score over 6 indicates that the patient is unlikely to survive without a transplant if treated with penicillamine. Two of our patients had Nazer scores higher than 6. With our medical therapy, all 9 of these patients have recovered normal liver function as reflected by normalization of their CTP scores to 5. Because of coexisting neurologic disease, 1 of our 9 patients was initiated on a neurologic protocol and by chance randomized to receive tetrathiomolybdate (TM) and zinc after 2 weeks of trientine/zinc treatment. This patient's liver function recovered much more rapidly than did that of the other 8 patients, all of whom were treated with trientine/zinc, suggesting that TM therapy offers a further advantage. In summary, we were able to take 9 patients who presented with liver failure -8 of whom had CTP scores indicating a potential need for liver transplantation and 2 of whom had Nazer prognostic scores indicating that they were not likely to survive if treated only with penicillamine - and treat them medically, with recovery in all 9. We believe the trientine/zinc combination therapy should be the standard for initial treatment of liver failure in Wilson's disease because its efficacy is equal or slightly superior to that of penicillamine and because it has a much lower incidence of side effects. Moreover, TM warrants study to determine whether therapy for hepatic Wilson's disease can be further improved.

Objective: To describe a patient with idiopathic zinc overload without an identifiable source and secondary copper deficiency causing myelopolyneuropathy and pancytopenia., Design: Case report., Patient and Results: A 46-year-old man presented with severe bone marrow suppression and subsequently developed progressive myelopathy with sensory ataxia. No identifiable cause of myelopathy was detected, and his neuroimaging findings were unremarkable. Plasma analysis demonstrated a low copper level and an increased zinc level (<10 micro g/dL [<12.6-18.9 micro mol/L] and 184 micro g/dL [28.2 micro mol/L], respectively; normal range for both, 80-120 micro g/dL [12.6-18.9 micro mol/L and 12.3-18.4 micro mol/L, respectively) and a low level of ceruloplasmin. There was no evidence for an external source of zinc. Daily oral supplementation with 2 mg resulted in the prompt reversal of hematologic abnormalities, improved but still subnormal plasma copper levels, and normalization of ceruloplasmin values. The patient's neurologic condition deteriorated further, with worsening of myelopathy and development of polyneuropathy. Analyses of plasma copper and zinc levels demonstrated persisting hyperzincemia and subnormal copper levels during 4 years of follow-up. Increased copper supplementation to 8 mg/d partially reversed his neurologic signs. A clinical investigation of 6 siblings and 1 surviving parent did not identify family members with similar abnormalities., Conclusions: Persistent hyperzincemia without an identifiable external source appears to be a primary metabolic defect, while copper deficiency is a secondary phenomenon, causing hematologic and neurologic abnormalities. Two unrelated patients with similar idiopathic hyperzincemia and hypocupremia have been recently described. This suggests the existence of a new metabolic disorder with idiopathic zinc overload.

Background: It is unclear what anticopper drug to use for patients with Wilson disease who present with neurologic manifestations because penicillamine often makes them neurologically worse and zinc is slow acting., Objective: To evaluate the frequency of neurologic worsening and drug adverse effects with ammonium tetrathiomolybdate., Design: Open-label study of 55 untreated patients (22 of them new) presenting with neurologic Wilson disease treated with tetrathiomolybdate varying from 120 to 410 mg/d for 8 weeks and then followed up for 3 years. Neurologic function was assessed with scored neurologic and speech tests., Setting: A university hospital referral setting., Patients: All untreated, newly diagnosed patients with neurologic Wilson disease., Intervention: Treatment with tetrathiomolybdate., Main Outcome Measures: Neurologic function was evaluated by neurologic and speech examinations. Drug adverse effects were evaluated by complete blood cell counts and biochemical measures., Results: Only 2 (4%) of 55 patients treated with tetrathiomolybdate showed neurologic deterioration, compared with an estimated 50% of penicillamine-treated patients. Five of the 22 new patients exhibited bone marrow suppression and 3 had aminotransferase elevations. These numbers are higher than in the original 33 patients and appear to be due primarily to a more rapid dose escalation., Conclusions: Tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur.

We are in the midst of an epidemic of Alzheimer's disease (AD) in developed countries. We have postulated that ingestion of inorganic copper from drinking water and taking supplement pills and a high fat diet are major causative factors. Ingestion of inorganic copper can directly raise the blood free copper level. Blood free copper has been shown by the Squitti group to be elevated in AD, to correlate with cognition, and to predict cognition loss. Secondly, we have shown that AD patients are zinc deficient compared to age matched controls. Zinc is important in neuronal protection. We carried out a 6-month small double blind trial of a new zinc formulation on AD patients. We found that in patients 70 years and older, zinc therapy protected against cognition decline compared to placebo controls.We also found that zinc therapy significantly lowered blood free copper levels. So zinc efficacy could be due to restoring neuronal zinc levels, to lowering blood free copper levels, or to both. [ABSTRACT FROM AUTHOR]

Abstract: It is clear that copper accumulation and toxicity is the cause of Wilson’s disease. It is also well established that zinc therapy is effective in treating Wilson’s disease by a mechanism of blocking intestinal copper absorption. An emerging hypothesis holds that ingestion of inorganic copper, such as from drinking water, plays a causal role in Alzheimer’s disease. The evidence behind this theory is discussed. There is good preliminary evidence that zinc therapy slows cognition loss in Alzheimer’s disease, either by repleting zinc in zinc deficient neurons, or by lowering the body’s free copper levels. Finally, evidence is presented on a variety of animal models and one human disease (primary biliary cirrhosis) that by lowering copper levels using a drug called tetrathiomolybdate, inflammatory fibrotic, and immune-modulated disease processes are benefitted. [Copyright &y& Elsevier]

Anticopper drugs that have been developed to treat Wilson''s disease, a disease of copper toxicity, include tetrathiomolybdate, zinc, penicillamine, and trientine. Lowering copper levels by a modest amount in non-Wilson''s patients with tetrathiomolybdate inhibits angiogenesis, fibrosis and inflammation while avoiding clinical copper deficiency. Through this mechanism tetrathiomolybdate has proven effective in numerous animal models of cancer, retinopathy, fibrosis, and inflammation. Penicillamine has efficacy in rheumatoid arthritis and trientine has efficacy in diabetic neuropathy and diabetic heart disease. If clinical studies support the animal work, anticopper therapy holds promise for therapy of cancer, fibrotic disease and inflammatory and autoimmune diseases. [Copyright &y& Elsevier]

Wilson's disease is a rare autosomal recessive disease of copper accumulation and copper toxicity, due to mutations in the ATP7B gene, which leads to a failure of copper excretion in the bile. It presents clinically primarily as liver disease, psychiatric disease, neurological disease, or a combination of these. The neurological disease is a movement disorder, with abnormalities of speech, tremor, incoordination and dystonia being common features. Diagnosis of neurologically presenting patients is usually straightforward, with Kayser-Fleischer rings and a urine copper over 100 microg/day almost invariably present. In the treatment of neurologically presenting patients, penicillamine should always be avoided, because of the high risk of permanent, drug-induced, additional neurological deterioration. A new drug we have developed, tetrathiomolybdate, given for 8-16 weeks, in combination with zinc, is our first choice for treating these patients. In the absence of availability of tetrathiomolybdate, zinc or trientine are the next best choices. [ABSTRACT FROM AUTHOR]

Responds to a letter to the editor about the role of copper deficiency or zinc excess myelopolyneuropathy.