Abnormal Copper Metabolism Research Articles

Bilateral Aneurysm of the Internal Jugular Vein Associated with Menkes Disease: Diagnosis, Risk Factors and Management

Menkes disease is a rare genetic disease due to an abnormality in copper metabolism. Clinical picture mainly includes neurological and cutaneous symptoms, and may present vascular complications. We report two cases of bilateral aneurysms of the internal jugular vein associated with Menkes disease, which were discovered by the appearance of cervical swellings a few months after birth. Diagnosis was set by Doppler ultrasonography and no specific treatment was decided for both cases. A review of literature then presents the diagnosis method, risk factors and management of aneurysms of the internal jugular vein in Menkes disease.

Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1.

Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu(2+) transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the σ1 subunit of the clathrin adaptor AP-1. Under basal Cu(2+) conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative σ1 mutant resulted in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Furthermore, addition of high Cu(2+) concentrations, previously shown to reduce ATP7B incorporation into AP-1-containing clathrin-coated vesicles, caused loss of TGN localization and somatodendritic polarity of ATP7B. These findings support the notion of AP-1 as an effector of polarized sorting in neurons and suggest that altered polarity of ATP7B in polarized cell types might contribute to abnormal copper metabolism in the MEDNIK syndrome, a neurocutaneous disorder caused by mutations in the σ1A subunit isoform of AP-1.

Abnormal copper metabolism in Niemann–Pick disease type C mimicking Wilson's disease

AbstractBackgroundNiemann–Pick disease type C is a rare lysosomal storage disease in infants, adolescents and adults.AimWe investigated a family with two siblings who have adult‐onset Niemann–Pick disease type C presenting with abnormal copper metabolism mimicking Wilson's disease.MethodsCase 1 was a 26‐years‐old Japanese man without consanguinity, and was referred to the hospital outpatient clinic for recent gait disturbance and intellectual deterioration developing since the age of 20 years. He was tentatively diagnosed as a heterozygous carrier of Wilson's disease, because his brother (case 2) had been diagnosed with Wilson's disease. He presented with dementia, dysphagia, dystonia, ataxia and downward gaze palsy. Laboratory study showed mild liver dysfunction and moderate splenomegaly. Magnetic resonance images showed a thin corpus callosum and narrowed deep white matter. Case 2 35 years‐of‐age, and had developed psychiatric and motor symptoms since 20 years‐of‐age. He had been treated for Wilson's disease for 11 years due to a copper deposit in his liver and abnormal copper metabolism. Symptoms had exacerbated gradually despite chelation therapy and tube feeding with gastrostomy for a year. Molecular diagnostics for Niemann–Pick disease type C were carried out.ResultsFilipin staining in cultured skin fibroblasts of case 1 was partially positive, and gene analysis showed that both siblings had compound heterozygosity for p.G992R in exon 20 and IVS6‐3 C>G of NPC1. Administration of miglustat for 3 months partially ameliorated their intellectual and motor dysfunction.ConclusionThe differential diagnosis between Niemann–Pick disease type C and Wilson's disease is important for specific treatment.

P957: Mixed-type polyneuropathy in Wilson's disease

Wilson’s Disease (WD) is an autosomal recessive disorder of abnormal copper metabolism witch predominantly affects the central nervous system and the liver. Peripheral nervous system involvement is rarely reported in the context of WD and not well characterized. Here we describe a WD patient with peripheral neuropathy. A 58-year-old male suffering from WD on therapy with trientine referred to our center because of mild distal limb weakness with hypoesthesia. Clinical evaluation showed mild leg weakness with foot drop and hyporreflexia. A nerve conduction study was performed using standard techniques (Medtronic Keypoint v5.09). Distal motor latency, F-wave latency, motor nerve conduction velocity and CMAP were evaluated in the deep peroneal, posterior tibial, median and ulnar nerves; sensory nerve conduction velocity and SAP were measured in the sural, superficial peroneal, median, ulnar and radial nerve. No other cause of polyneuropathy was found. Electroneurographyc findings suggested an asymmetric length-dependent sensory-motor neuropathy of mixed type. We confirmed peripheral nervous system involvement in WD. According to the literature, also our findings showed both myelin and axonal damage. Polyneuropathy may appear despite therapy, although a iatrogenic contribution cannot be excluded.

Toxicity of Copper on Isolated Liver Mitochondria: Impairment at Complexes I, II, and IV Leads to Increased ROS Production

Oxidative damage has been implicated in disorders associated with abnormal copper metabolism and also Cu(2+) overloading states. Besides, mitochondria are one of the most important targets for Cu(2+), an essential redox transition metal, induced hepatotoxicity. In this study, we aimed to investigate the mitochondrial toxicity mechanisms on isolated rat liver mitochondria. Rat liver mitochondria in both in vivo and in vitro experiments were obtained by differential ultracentrifugation and the isolated liver mitochondria were then incubated with different concentrations of Cu(2+). Our results showed that Cu(2+) induced a concentration and time-dependent rise in mitochondrial ROS formation, lipid peroxidation, and mitochondrial membrane potential collapse before mitochondrial swelling ensued. Increased disturbance in oxidative phosphorylation was also shown by decreased ATP concentration and decreased ATP/ADP ratio in Cu(2+)-treated isolated mitochondria. In addition, collapse of mitochondrial membrane potential (MMP), mitochondrial swelling, and release of cytochrome c following of Cu(2+) treatment were well inhibited by pretreatment of mitochondria with CsA and BHT. Our results showed that Cu(2+) could interact with respiratory complexes (I, II, and IV). This suggests that Cu(2+)-induced liver toxicity is the result of metal's disruptive effect on liver hepatocyte mitochondrial respiratory chain that is the obvious cause of Cu(2+)-induced ROS formation, lipid peroxidation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling.

Insulin signaling and copper homeostasis are functionally linked in 3T3‐L1 adipocytes (992.2)

Copper is an essential element for human growth and development. Abnormal copper metabolism is associated with severe and potentially lethal disorders. Previous studies of copper misbalance in the animal model of Wilson’s disease have shown that copper levels influence cholesterol and triglyceride content in tissues. To understand the mechanisms connecting copper and lipid metabolism, we characterized copper homeostasis in 3T3‐L1 adipocytes upon differentiation and insulin signaling. We show that during adipogenesis copper uptake is upregulated 2‐3 fold. Protein levels of the copper‐transporting ATP7A also increase, presumably to facilitate copper delivery to semicarbazide‐sensitive amine oxidase (SSAO), a copper‐containing enzyme that exerts an insulin‐like effect and is highly upregulated in differentiated adipocytes. Both copper depletion and copper elevation inhibit SSAO’s activity, suggesting a fine‐tuned regulation of this enzyme by the metal. In turn, SSAO’s substrates and product regulate ATP7A localization in cells triggering trafficking form the trans‐Golgi network to vesicles. In response to insulin, copper uptake remains unchanged, whereas ATP7A traffics to the plasma membrane and vesicles indicating insulin‐dependent redistribution of intracellular copper pools. Altogether, our data revealed a novel metabolic connection between copper homeostasis and insulin signaling in differentiated adipocytes.* Equal contributionGrant Funding Source: NIH R01 GM101502

MR image mimicking the “eye of the tiger” sign in Wilson’s disease

Dear Sirs, The eye of the tiger sign (EOT), seen on T2 sequences of magnetic resonance imaging (MRI), is considered pathognomonic for neurodegeneration with brain iron accumulation type 1 (NBIA1, previously known as Hallervorden–Spatz syndrome) [1–3]. This sign is described as low signal intensity in both globi pallidi (due to iron accumulation) that surrounds a central region of high signal intensity (caused by gliosis, edema, and neuronal loss with subsequent secondary vacuolization and cavitation) [1–3]. It has been occasionally reported in neurodegenerative disorders other than NBIA1, including neuroferritinopathy, progressive supranuclear palsy, multisystem atrophy, pure akinesia, and corticobasal degeneration [1–3]. Here, we describe the first case of EOT-like MRI appearance in a 41-year-old man with Wilson’s disease. At the age of 24 years, the patient developed dysarthria, oromandibular dystonia, gait disturbances, and positional hand tremor. One year later he was diagnosed with Wilson’s disease, based on the presence of Kayser–Fleischer ring and abnormal copper metabolism [i.e. decreased serum ceruloplasmin (8.2 mg/dL, normal 25–45) and serum copper (30 μg/dL, normal 70–140 μg/dL) combined with increased copper urinary excretion (664 μg/24 h, normal 0–50)]. Genetic examination confirmed compound heterozygosity, with ATP7B mutations in exon 13 (G988R) and in exon 7 (IVS7 + 3A>G). After introduction of 1000 mg/day d-penicillamine, the patient gradually improved. In 2013 his remaining symptoms were only slight dysarthria and oromandibular dystonia (occasionally grimacing). The Kayser–Fleischer rings were no longer present. However, a routine control brain MRI revealed abnormalities very similar to EOT sign (Fig. 1). Fig. 1 The MR image mimicking the “eye of the tiger” sign in T2-weighted magnetic resonance sequences; bilateral hypointensity in both putaminal regions and lateral parts of globi pallidi, with a central hyperintensity (black arrows) The difference was that hypointensity tended to localize in the lateral part of the globus pallidus and putamen instead of the medial part of the globus pallidus. Subsequent MR spectroscopy showed that the mean N-acetyloaspartate/creatine ratio (TE-144mS) in the globus pallidus was 1.55, and the mean choline/creatine ratio (TE-144 mS) was 1.10 (Fig. 2a). In the normal appearing control region, the values were 2.37 and 1.08, respectively (Fig. 2b), which may reflect neuronal loss in the affected area. Noteworthy, the patient has no co-morbidities, does not drink alcohol and had no occupational risk factors for tissue metal accumulation. Normal levels of serum iron metabolism markers (ferritin, iron, total iron binding capacity) combined with the early age of the disease onset, lack of anemia and diabetes allowed to exclude aceruloplasminemia and neuroferritinopathy. The lack of acanthocytosis, pigmentary retinopathy, hypoprobetalipoproteinemia, and good response to d-penicillamine with no subsequent progression over 15 years allowed us to exclude NBIA1. The patient's brother was diagnosed with hepatic Wilson’s disease without any neurological signs at 28 years of age. Fig. 2 The magnetic brain spectroscopy from: a unaffected structures in the right temporal lobe; b central, hyperintensive part of “eye of the tiger” sign showing markedly decreased N-acetyloaspartate in the globus pallidus as a results of reactive ... Wilson’s disease is a treatable, inherited disorder leading to pathological copper accumulation that damages affected organs, especially the liver and brain. It has been suggested that disturbances of iron metabolism occur in the liver of Wilson’s disease patients, as copper-dependent enzymes are also involved in its metabolic pathways [4]. In a recent post-mortem study we demonstrated that iron accumulates also in the brain [5]. As the EOT sign suggests accumulation of iron [2, 3, 6, 7], its increased concentration in the basal ganglia of the reported patient appeared to be particularly pronounced. However, the exact role of iron-metabolism disturbances in Wilson’s disease is still unknown and further studies are needed. Considering that patients with EOT sign may occasionally have conditions other than NBIA1, it is advisable to carry out careful differential diagnosis in order not to miss a condition that can be effectively treated.

Pathogenesis and management of Wilson disease

Hepatolenticular degeneration, commonly known as Wilson disease, is an autosomal recessive inherited disease of abnormal copper metabolism, characterized by the accumulation of copper in the body due to decreased biliary excretion of copper from hepatocytes. Wilson disease protein, ATP7B, functions in copper excretion into bile and in copper secretion to the bloodstream coupled with ceruloplasmin synthesis. Various kinds of mutations of ATP7B cause Wilson disease. Wilson disease is a rare genetic disease that can be treated pharmacologically. Recognition and prompt diagnosis are very important, because Wilson disease is fatal if left untreated. In this review, I summarize the pathogenesis and management of Wilson disease.

A neuropsychological comparison of siblings with neurological versus hepatic symptoms of Wilson’s Disease

Wilson’s Disease (WD) (also known as hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of abnormal copper metabolism, with an estimated prevalence of approximately 1 in 30,000. The clinical features associated with WD are highly varied. However, subtypes generally reflect neurological, hepatic, and psychiatric symptoms. The present case study reports two brothers with a recent diagnosis of WD. Neurological symptoms and cognitive deficits were exhibited in one brother (BL) in the form of extrapyramidal features, while the other brother (AL) only exhibited hepatic symptoms. Extensive neuropsychological testing was conducted on both siblings to compare cognitive profiles. Results for BL indicated significantly impaired motor functioning and information processing speed, which impacted him significantly at school. Aspects of executive dysfunction were also apparent in addition to reduced visual and verbal memory, working memory, and attention. Results for AL revealed evidence of verbal memory difficulties and aspects of executive dysfunction. Comparison is made of the distinct and common cognitive characteristics of the cases presented in terms of implications for early intervention and management of cognitive difficulties.

70. Mixed-type polyneuropathy in Wilson’s Disease

Wilson’s Disease (WD) is an autosomal recessive disorder of abnormal copper metabolism witch predominantly affects the central nervous system and the liver. Peripheral nervous system involvement is rarely reported in the context of WD and not well characterized. Here we describe a WD patient with peripheral neuropathy. A 58-year-old male suffering from WD on therapy with trientine referred to our center because of mild distal limb weakness with hypoesthesia. Clinical evaluation showed mild leg weakness with foot drop and hyporreflexia. A nerve conduction study was performed using standard techniques (Medtronic Keypoint v5.09). Distal motor latency, F-wave latency, motor nerve conduction velocity and CMAP were evaluated in the deep peroneal, posterior tibial, median and ulnar nerves; sensory nerve conduction velocity and SAP were measured in the sural, superficial peroneal, median, ulnar and radial nerve. No other cause of polyneuropathy was found. Electroneurographyc findings suggested an asymmetric length-dependent sensory-motor neuropathy of mixed type. We confirmed peripheral nervous system involvement in WD. According to the literature, also our findings showed both myelin and axonal damage. Polyneuropathy may appear despite therapy, although a iatrogenic contribution cannot be excluded.

Recognition and Treatment of Neurologic Wilson's Disease

As Wilson's disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilson's disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilson's disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective.

Links between copper and cholesterol in Alzheimer's disease

Altered copper homeostasis and hypercholesterolemia have been identified independently as risk factors for Alzheimer's disease (AD). Abnormal copper and cholesterol metabolism are implicated in the genesis of amyloid plaques and neurofibrillary tangles (NFT), which are two key pathological signatures of AD. Amyloidogenic processing of a sub-population of amyloid precursor protein (APP) that produces Aβ occurs in cholesterol-rich lipid rafts in copper deficient AD brains. Co-localization of Aβ and a paradoxical high concentration of copper in lipid rafts fosters the formation of neurotoxic Aβ:copper complexes. These complexes can catalytically oxidize cholesterol to generate H2O2, oxysterols and other lipid peroxidation products that accumulate in brains of AD cases and transgenic mouse models. Tau, the core protein component of NFTs, is sensitive to interactions with copper and cholesterol, which trigger a cascade of hyperphosphorylation and aggregation preceding the generation of NFTs. Here we present an overview of copper and cholesterol metabolism in the brain, and how their integrated failure contributes to development of AD.

Copper and Anesthesia: Clinical Relevance and Management of Copper Related Disorders

Recent research has implicated abnormal copper homeostasis in the underlying pathophysiology of several clinically important disorders, some of which may be encountered by the anesthetist in daily clinical practice. The purpose of this narrative review is to summarize the physiology and pharmacology of copper, the clinical implications of abnormal copper metabolism, and the subsequent influence of altered copper homeostasis on anesthetic management.

Neuromuscular Electrical Stimulation Therapy for Dysphagia Caused by Wilson's Disease.

Wilson's disease is an autosomal recessive disorder of abnormal copper metabolism. Although dysphagia is a common complaint of patients with Wilson's disease and pneumonia is an important cause of death in these patients, management of swallowing function has rarely been reported in the context of Wilson's disease. Hence, we report a case of Wilson's disease presenting with dysphagia. A 33-year-old man visited our hospital with a complaint of difficulty in swallowing, since about last 7 years and which had worsened since the last 2-3 months. He was diagnosed with Wilson's disease about 13 years ago. On the initial VFSS, reduced hyoid bone movement, impaired epiglottic movement and moderate amount of residue in the valleculae during the pharyngeal phase were noted. After 10 sessions of neuromuscular electrical stimulation for 1 hour per day, decreased amount of residue was observed in the valleculae during the pharyngeal phase on the follow-up VFSS.

Diagnosis of Copper Transport Disorders

Techniques for the diagnosis of copper transport disorders are increasingly important due to recent recognition of previously unappreciated clinical phenotypes and emerging advances in the treatment of these conditions. Here, we collate the diagnostic approaches and techniques currently employed for biochemical and molecular assessment of at-risk individuals in whom abnormal copper metabolism is suspected.

Clinical and diagnostic approach in unsolved CDG patients with a type 2 transferrin pattern

Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999–2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect. Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability.

Positron Emission Tomography of Copper Metabolism in the Atp7b −/− Knock-out Mouse Model of Wilson’s Disease

This study aims to determine feasibility and utility of copper-64(II) chloride (⁶⁴CuCl₂) as a tracer for positron emission tomography (PET) of copper metabolism imbalance in human Wilson's disease (WD). Atp7b⁻/⁻ mice, a mouse model of human WD, were injected with ⁶⁴CuCl₂ intravenously and subjected to PET scanning using a hybrid PET-CT (computerized tomography) scanner, with the wild-type C57BL mice as a normal control. Quantitative PET analysis was performed to determine biodistribution of ⁶⁴Cu radioactivity and radiation dosimetry estimates of ⁶⁴Cu were calculated for PET of copper metabolism in humans. Dynamic PET analysis revealed increased accumulation and markedly reduced clearance of ⁶⁴Cu from the liver of the Atp7b⁻/⁻ mice, compared to hepatic uptake and clearance of ⁶⁴Cu in the wild-type C57BL mice. Kinetics of copper clearance and retention was also altered for kidneys, heart, and lungs in the Atp7b/⁻ mice. Based on biodistribution of ⁶⁴Cu in wild-type C57BL mice, radiation dosimetry estimates of ⁶⁴Cu in normal human subjects were obtained, showing an effective dose (ED) of 32.2 μ (micro)Sv/MBq (weighted dose over 22 organs) and the small intestine as the critical organ for radiation dose (61 μGy/MBq for males and 69 μGy/MBq for females). Radiation dosimetry estimates for the patients with WD, based on biodistribution of ⁶⁴Cu in the Atp7b⁻/⁻ mice, showed a similar ED of 32.8 μ (micro)Sv/MBq (p = 0.53), with the liver as the critical organ for radiation dose (120 μSv/MBq for male and 161 μSv/MBq for female). Quantitative PET analysis demonstrates abnormal copper metabolism in the mouse model of WD with improved time-resolution. Human radiation dosimetry estimates obtained in this preclinical study encourage direct radiation dosimetry of ⁶⁴CuCl₂ in human subjects. The results suggest feasibility of utilizing ⁶⁴CuCl₂ as a tracer for noninvasive assessment of copper metabolism in WD with PET.

Lingual Dyskinesia and Tics: A Novel Presentation of Copper-Metabolism Disorder

Copper is a trace element that is required for cellular respiration, neurotransmitter biosynthesis, pigment formation, antioxidant defense, peptide amidation, and formation of connective tissue. Abnormalities of copper metabolism have been linked with neurologic disorders that affect movement, such as Wilson disease and Menkes disease; however, the diagnosis of non-Wilson, non-Menkes-type copper-metabolism disorders has been more elusive, especially in cases with atypical characteristics. We present here the case of an adolescent with a novel presentation of copper-metabolism disorder who exhibited acute severe hemilingual dyskinesia and prominent tics, with ballismus of the upper limbs, but had normal brain and spinal MRI results and did not show any signs of dysarthria or dysphagia. His serum copper and ceruloplasmin levels were low, but his urinary copper level was elevated after penicillamine challenge. We conclude that copper-metabolism disorders should be included in the differential diagnosis for movement disorders, even in cases with highly unusual presentations, because many of them are treatable. Moreover, a connection between copper-metabolism disorders and tics is presented, to our knowledge, for the first time in humans; further investigation is needed to better establish this connection and understand its underlying pathophysiology.

An Unusual Presentation of Copper Metabolism Disorder and a Possible Connection With Niemann-Pick Type C

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency-dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.

Paradigm Shift in Treatment of Alzheimer′s Disease: Zinc Therapy Now a Conscientious Choice for Care of Individual Patients

Breakthrough in treatment of Alzheimer's disease with a shift from irrational dangerous chelation therapy to rational safe evidence based oral zinc therapy. Evidence based medicine: After synthesizing the best available clinical evidence I conclude that oral zinc therapy is a conscientious choice for treatment of free copper toxicosis in individual patients with Alzheimer's disease. Hypothesis 1: Age related free copper toxicosis is a causal factor in pathogenesis of Alzheimer's disease. There are 2 neurodegenerative diseases with abnormalities in copper metabolism: (a) the juvenile form with degeneration in the basal ganglia (Wilson's disease) and (b) the age related form with cortical neurodegeneration (Alzheimer's disease). Initially the hypothesis has been that neurodegeneration was caused by accumulation of copper in the brain but later experiences with treatment of Wilson's disease led to the conviction that free plasma copper is the toxic form of copper: it catalyzes amyloid formation thereby generating oxidative stress, free radicals and degeneration of cortical neurons. Hypothesis 2: Oral zinc therapy is an effective and safe treatment of free copper toxicosis in Alzheimer's disease. Proposed dosage: 50 mg elementary zinc/day. Warning: Chelation therapy is irrational and dangerous in treatment of copper toxicosis in Alzheimer's disease.