89
Journal of Alzheimer’s Disease 46 (2015) 89–92 DOI 10.3233/JAD-150186 IOS Press
Commentary
Zinc and Copper in Alzheimer’s Disease Abolfazl Avana and Tjaard U. Hoogenraadb,∗ a Department b Department
of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands
Accepted 13 March 2015
Abstract. In a recent meta-analysis by Ventriglia and colleagues studying the association of zinc levels with Alzheimer’s disease (AD), serum zinc has been found significantly decreased in AD patients compared with healthy controls. However, such a finding does not necessarily propose the causal role of low zinc in the pathophysiology of this neurodegenerative disease. On the basis of available evidence, free copper toxicosis may play a causal role in age-related AD, and zinc therapy can be a rational causal treatment. Nevertheless, a randomized controlled clinical trial testing a definite hypothesis is needed before conclusions can be drawn about the value of zinc supplements in the treatment of AD. Keywords: Alzheimer’s disease, ceruloplasmin, copper, free copper, metallothionein, neurodegeneration, underreporting, Wilson’s disease, zinc
INTRODUCTION In the current issue of the Journal of Alzheimer’s disease (JAD), Ventriglia et al. [1] revealed the results of a meta-analysis evaluating the association of zinc levels in serum, plasma, and cerebrospinal fluid with Alzheimer’s disease (AD) in 27 studies. In view of the heterogeneity of the enrolled studies, they speculated that the significantly lower zinc values in serum and plasma of AD patients compared to healthy controls might be associated with AD [1]. Editor-in-Chief of JAD, George Perry, invited T.U. Hoogenraad (TUH), to review the paper. In TUH’s opinion, the manuscript is very important to the field of AD and deserves a place in the journal. Highlighting the importance of zinc in the etiology and prevention of AD. However, three points require further clarification including: 1) the danger of underreporting; 2) the role of free copper intoxication in the etiology of AD; ∗ Correspondence to: Dr. Tjaard U. Hoogenraad, MD, PhD, Van Galenlaan 20, 3941 VD, Doorn, Utrechtse Heuvelrug, the Netherlands. Tel.: +31 343 413 519; E-mail: tu.hoogenraad@ planet.nl.
and 3) the importance of zinc therapy in the treatment of copper toxicosis. AD is a common form of dementia with a high burden, which made it a global health concern. However, the mechanism of neurodegeneration has remained ambiguous. Different hypotheses have been proposed so far concerning the cause of AD, which imply the multifactorial nature of this progressive neurodegenerative disease of aging. Aggregation of amyloid- protein in different compartments is one of the hypotheses. Neuropathological research has shown that the plaques detected in the brain of patients with AD contain deposits of amyloid and abnormal neurofibrils, and thus the cortical neurons being withered. However, some evidence suggests these pathologies as by-products of impaired metal metabolism. To develop a causal therapy for AD, we first need to understand the etiology of the disease. During the last two decades, among the four main risk factors for AD, i.e., inflammatory, vascular, environmental, and genetic factors, high free copper has shown promising evidence in favor of association with the etiology of AD. Free copper generates reactive oxy-
ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
90
A. Avan and T.U. Hoogenraad / Zinc and Copper in Alzheimer’s Disease
gen species such as superoxide, hydrogen peroxide, the hydroxyl radical that ruin proteins, lipids and DNA. It is postulated that hypermetallation of the A peptide is at the basis of reduction-oxidation (redox) cycles of oxidative stress, which result in A oligomer formations that are packed together with metals within plaques (discussed in [2]). We believe that AD shares many common features with Wilson’s disease (WD) in terms of etiology and potential treatment and thus the success of zinc therapy in WD can possibly apply to AD as well. WD has been known as progressive lenticular degeneration reflecting the neurodegeneration of the basal ganglia. Thus, TUH hypothesized the existence of two types of free copper diseases, namely type 1 (juvenile) free copper toxicosis that is WD, and type 2 (age-related, senile) free copper toxicosis that is AD [2]. ALZHEIMER TYPE I AND II ASTROCYTES: LINKING TYPE 1 AND TYPE 2 COPPER DISEASES In 1912, Von Hoesslin and Alzheimer, unaware of WD, published a report of the clinical and pathological findings in a patient with pseudosclerosis. WD and pseudosclerosis were at that time regarded as being distinct diseases (adopted from the monograph “Wilson’s disease” [3]). The macroscopic findings in the brain were unremarkable and, in contrast to WD, no cavitation was observed in the lentiform nucleus. However, in the microscopic features, abnormal glial cells were prominent. Some cells showed a swollen, hyperchromatic nucleus and many green granules in the protoplasm (Alzheimer type 1 astrocytes). More frequently, glia cells were seen with pale enlarged vesicular nuclei and many infoldings of the nuclear membrane, giving an impression of multiple nuclei (Alzheimer type II astrocytes). Many of these cells had a diameter two or three times larger than normal. Most neurons had a normal appearance, while in the cerebral cortex and putamen, degenerated ganglion cells were detected. The most conspicuous abnormalities were found in the dentate nucleus and corpus striatum, but the thalamus, subthalamus, cortex, and pons cerebra were also severely affected. Alzheimer suggested that these novel findings might be characteristic for pseudosclerosis. He did not comment on an association between these abnormalities and liver cirrhosis. Having reviewed the neuropathology of WD and pseudosclerosis, in 1920, Spielmeyer came to the conclusion that these two conditions were identical. Now we know that swollen astrocytes in WD contain
the metal-binding protein metallothioneins, which may be involved in the process of copper detoxification [4].
TRAGIC UNDERREPORTING Over the last 60 years, copper accumulation has been regarded as the cause of WD. This is because an increased concentration of copper has been detected in different vital organs, particularly liver and brain. Thus, chelators, such as dimercaprol, penicillamine, and trientine, were speculated effective in terms of mobilizing copper by making the detoxified bound-copper into free toxic form. Chelators are regarded to stimulate the excretion of free copper via the urine and thus decrease the copper content. However, as the result of this iatrogenic increase in serum free copper levels, many patients deteriorate on chelators and some never recover. The same concept has been utilized to diagnosis of pediatric population with symptomatic WD using the D -penicillamine challenge test (>1575 g/24 hours urine copper after 1 g penicillamine). Nevertheless, with regard to its low sensitivity and unsatisfactory diagnostic accuracy [5], it may have no advantage to urine copper excretion combined with measurement of serum ceruloplasmin for the diagnosis of WD [6]. On the basis of potential role of copper in AD, implication of penicillamine in AD patients has been tested in a randomized controlled clinical trial [7]. However, they did not find significant differences in AD progression between D -penicillamine and placebo groups. Moreover, they emphasized that whenever changes are observed, the D -penicillamine group showed a worse evolution, which highlights the toxic effect of iatrogenic copper intoxication. In contrast to the previous hypothesis, in 1961, the clinical neurologist Gerrit Schouwink postulated that the induction of a negative copper balance via halting intestinal copper absorption would be a rational strategy in treating copper intoxication in WD. However, the results have only been published in Dutch and remained unknown for years until TUH, noted the importance of the scientific comparative study by Schouwink and reported the efficacy of zinc therapy in WD [8]. Now, the treatment of symptomatic Wilson’s disease is no longer advised to aim at ‘decoppering’, the removal of accumulated copper, but at the normalization of the free copper concentration in blood, to reverse the copper poisoning [3]. Thus, as a consequence of this underreporting, for years patients have been deprived of an effective and safe treatment.
A. Avan and T.U. Hoogenraad / Zinc and Copper in Alzheimer’s Disease
ZINC THERAPY IN COPPER INTOXICATION Increased unbound or loosely-bound copper in serum is toxic and may induce neurodegeneration through oxidation and generation of free radicals [9]. Thus, a raised level of urinary and serum free copper are used as diagnostic tools. Taking the data from Schouwink’s experience, along with some further investigations that were performed in the Netherlands, there have been enough evidence to advocate zinc monotherapy as a safe and effective treatment of free copper intoxication (discussed in [10]). Zinc induces the production of intestinal metallothioneins, which will lead to increased excretion of free copper via the stool. Thus, TUH [3, 10] proposed zinc, which benefits efficacy, safety, and affordability, as initial treatment for copper toxicosis in WD. Serum concentration of copper and zinc are tightly intertwined, and an increase in the copper:zinc ratio in the elderly usually reflects an inflammatory response (reviewed in [11]). An increased ratio might drive systemic signals that resume maintenance and repair, whereas, a decreased ratio would be suggestive of promoting signals that regulate cellular proliferation and growth [11]. In summary, conscientious analytic cumulating of the available evidence has led to the hypothesis that free copper toxicosis does catalyze formation of amyloid in plaques and oxidative stress causing neurodegeneration in AD [9]. Although our knowledge of copper in AD is scarce and diverse (reviewed in [12]), in vitro and in vivo as well as recent genetic data [13], along with meta-analyses [14], sustain a systemic deregulation of copper in AD. Dyshemostasis in metals suggests a zinc-dependent immune response to the gradual development of aberrant metal hemostasis, oxidative stresses, and inflammation. An increase in zinc levels provokes metallothionein expression, which is a reactive response to neuronal damage, increased inflammation, and increased oxidative stress (discussed in [15]).
ever, the impact of this study would have been much improved if they had followed the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) guideline for systematic review and metaanalysis [16]. Thus, on the basis of available evidence, we echo the hypothesis that free copper toxicosis may play a causal role in age-related AD, and zinc therapy can be a rational causal treatment. A randomized controlled clinical trial testing a definite hypothesis is needed before conclusions can be drawn about the value of zinc supplements in the treatment of AD. DISCLOSURE STATEMENT Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/15-0186r1). REFERENCES [1]
[2]
[3]
[4]
[5]
[6]
[7]
[8] [9]
CONCLUSION We believe studies on zinc and copper may result in a breakthrough in the management of AD. The authors [1] cautiously indicated that serum zinc was significantly decreased in AD patients compared with healthy controls. This finding, despite the limitations acknowledged in their manuscript, may indeed support the metal hypothesis in the etiology of AD. How-
91
[10] [11]
[12]
Ventriglia M, Brewer GJ, Simonelli I, Mariani S, Siotto M, Bucossi S, Squitti R (2015) Zinc in Alzheimer’s disease: A meta-analysis of serum, plasma, and cerebrospinal fluid studies. J Alzheimers Dis 46, doi: 10.3233/JAD-141296 Hoogenraad TU (2011) Paradigm shift in treatment of Alzheimer’s disease: Zinc therapy now a conscientious choice for care of individual patients. Int J Alzheimers Dis 2011, 492686. Hoogenraad TU (2006) Paradigm shift in treatment of Wilson’s disease: Zinc therapy now treatment of choice. Brain Dev 28, 141-146. Bertrand E, Lewandowska E, Szpak GM, Hoogenraad T, Blaauwgers HG, Czlonkowska A, Dymecki J (2001) Neuropathological analysis of pathological forms of astroglia in Wilson’s disease. Folia Neuropathol 39, 73-79. Nicastro E, Ranucci G, Vajro P, Vegnente A, Iorio R (2010) Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology 52, 1948-1956. Schilsky ML (2007) Non-invasive testing for Wilson disease: Revisiting the d-penicillamine challenge test. J Hepatol 47, 172-173. Squitti R, Rossini PM, Cassetta E, Moffa F, Pasqualetti P, Cortesi M, Colloca A, Rossi L, Finazzi-Agro A (2002) dpenicillamine reduces serum oxidative stress in Alzheimer’s disease patients. Eur J Clin Invest 32, 51-59. Hoogenraad TU, Van den Hamer CJ, Koevoet R, Korver EG (1978) Oral zinc in Wilson’s disease. Lancet 2, 1262. Atwood CS, Huang X, Khatri A, Scarpa RC, Kim YS, Moir RD, Tanzi RE, Roher AE, Bush AI (2000) Copper catalyzed oxidation of Alzheimer Abeta. Cell Mol Biol (Noisy -legrand) 46, 777-783. Hoogenraad TU (1996) Wilson’s disease. In: Major Problems in Neurology Series. Vol. 30, W B Saunders. Malavolta M, Piacenza F, Basso A, Giacconi R, Costarelli L, Mocchegiani E (2015) Serum copper to zinc ratio: Relationship with aging and health status. Mech Ageing Dev. Pal A, Siotto M, Prasad R, Squitti R (2015) Towards a unified vision of copper involvement in Alzheimer’s disease: A review connecting basic, experimental, and clinical research. J Alzheimers Dis 44, 343-354.
92 [13]
[14]
A. Avan and T.U. Hoogenraad / Zinc and Copper in Alzheimer’s Disease Squitti R, Polimanti R, Siotto M, Bucossi S, Ventriglia M, Mariani S, Vernieri F, Scrascia F, Trotta L, Rossini PM (2013) ATP7B variants as modulators of copper dyshomeostasis in Alzheimer’s disease. Neuromolecular Med 15, 515-522. Squitti R, Simonelli I, Ventriglia M, Siotto M, Pasqualetti P, Rembach A, Doecke J, Bush AI (2014) Meta-analysis of serum non-ceruloplasmin copper in Alzheimer’s disease. J Alzheimers Dis 38, 809-822.
[15] [16]
Aschner M, West AK (2005) The role of MT in neurological disorders. J Alzheimers Dis 8, 139-145. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP (2007) Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. BMJ 335, 806-808.
Journal of Alzheimer’s Disease 46 (2015) 89–92 DOI 10.3233/JAD-150186 IOS Press
Commentary
Zinc and Copper in Alzheimer’s Disease Abolfazl Avana and Tjaard U. Hoogenraadb,∗ a Department b Department
of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands
Accepted 13 March 2015
Abstract. In a recent meta-analysis by Ventriglia and colleagues studying the association of zinc levels with Alzheimer’s disease (AD), serum zinc has been found significantly decreased in AD patients compared with healthy controls. However, such a finding does not necessarily propose the causal role of low zinc in the pathophysiology of this neurodegenerative disease. On the basis of available evidence, free copper toxicosis may play a causal role in age-related AD, and zinc therapy can be a rational causal treatment. Nevertheless, a randomized controlled clinical trial testing a definite hypothesis is needed before conclusions can be drawn about the value of zinc supplements in the treatment of AD. Keywords: Alzheimer’s disease, ceruloplasmin, copper, free copper, metallothionein, neurodegeneration, underreporting, Wilson’s disease, zinc
INTRODUCTION In the current issue of the Journal of Alzheimer’s disease (JAD), Ventriglia et al. [1] revealed the results of a meta-analysis evaluating the association of zinc levels in serum, plasma, and cerebrospinal fluid with Alzheimer’s disease (AD) in 27 studies. In view of the heterogeneity of the enrolled studies, they speculated that the significantly lower zinc values in serum and plasma of AD patients compared to healthy controls might be associated with AD [1]. Editor-in-Chief of JAD, George Perry, invited T.U. Hoogenraad (TUH), to review the paper. In TUH’s opinion, the manuscript is very important to the field of AD and deserves a place in the journal. Highlighting the importance of zinc in the etiology and prevention of AD. However, three points require further clarification including: 1) the danger of underreporting; 2) the role of free copper intoxication in the etiology of AD; ∗ Correspondence to: Dr. Tjaard U. Hoogenraad, MD, PhD, Van Galenlaan 20, 3941 VD, Doorn, Utrechtse Heuvelrug, the Netherlands. Tel.: +31 343 413 519; E-mail: tu.hoogenraad@ planet.nl.
and 3) the importance of zinc therapy in the treatment of copper toxicosis. AD is a common form of dementia with a high burden, which made it a global health concern. However, the mechanism of neurodegeneration has remained ambiguous. Different hypotheses have been proposed so far concerning the cause of AD, which imply the multifactorial nature of this progressive neurodegenerative disease of aging. Aggregation of amyloid- protein in different compartments is one of the hypotheses. Neuropathological research has shown that the plaques detected in the brain of patients with AD contain deposits of amyloid and abnormal neurofibrils, and thus the cortical neurons being withered. However, some evidence suggests these pathologies as by-products of impaired metal metabolism. To develop a causal therapy for AD, we first need to understand the etiology of the disease. During the last two decades, among the four main risk factors for AD, i.e., inflammatory, vascular, environmental, and genetic factors, high free copper has shown promising evidence in favor of association with the etiology of AD. Free copper generates reactive oxy-
ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
90
A. Avan and T.U. Hoogenraad / Zinc and Copper in Alzheimer’s Disease
gen species such as superoxide, hydrogen peroxide, the hydroxyl radical that ruin proteins, lipids and DNA. It is postulated that hypermetallation of the A peptide is at the basis of reduction-oxidation (redox) cycles of oxidative stress, which result in A oligomer formations that are packed together with metals within plaques (discussed in [2]). We believe that AD shares many common features with Wilson’s disease (WD) in terms of etiology and potential treatment and thus the success of zinc therapy in WD can possibly apply to AD as well. WD has been known as progressive lenticular degeneration reflecting the neurodegeneration of the basal ganglia. Thus, TUH hypothesized the existence of two types of free copper diseases, namely type 1 (juvenile) free copper toxicosis that is WD, and type 2 (age-related, senile) free copper toxicosis that is AD [2]. ALZHEIMER TYPE I AND II ASTROCYTES: LINKING TYPE 1 AND TYPE 2 COPPER DISEASES In 1912, Von Hoesslin and Alzheimer, unaware of WD, published a report of the clinical and pathological findings in a patient with pseudosclerosis. WD and pseudosclerosis were at that time regarded as being distinct diseases (adopted from the monograph “Wilson’s disease” [3]). The macroscopic findings in the brain were unremarkable and, in contrast to WD, no cavitation was observed in the lentiform nucleus. However, in the microscopic features, abnormal glial cells were prominent. Some cells showed a swollen, hyperchromatic nucleus and many green granules in the protoplasm (Alzheimer type 1 astrocytes). More frequently, glia cells were seen with pale enlarged vesicular nuclei and many infoldings of the nuclear membrane, giving an impression of multiple nuclei (Alzheimer type II astrocytes). Many of these cells had a diameter two or three times larger than normal. Most neurons had a normal appearance, while in the cerebral cortex and putamen, degenerated ganglion cells were detected. The most conspicuous abnormalities were found in the dentate nucleus and corpus striatum, but the thalamus, subthalamus, cortex, and pons cerebra were also severely affected. Alzheimer suggested that these novel findings might be characteristic for pseudosclerosis. He did not comment on an association between these abnormalities and liver cirrhosis. Having reviewed the neuropathology of WD and pseudosclerosis, in 1920, Spielmeyer came to the conclusion that these two conditions were identical. Now we know that swollen astrocytes in WD contain
the metal-binding protein metallothioneins, which may be involved in the process of copper detoxification [4].
TRAGIC UNDERREPORTING Over the last 60 years, copper accumulation has been regarded as the cause of WD. This is because an increased concentration of copper has been detected in different vital organs, particularly liver and brain. Thus, chelators, such as dimercaprol, penicillamine, and trientine, were speculated effective in terms of mobilizing copper by making the detoxified bound-copper into free toxic form. Chelators are regarded to stimulate the excretion of free copper via the urine and thus decrease the copper content. However, as the result of this iatrogenic increase in serum free copper levels, many patients deteriorate on chelators and some never recover. The same concept has been utilized to diagnosis of pediatric population with symptomatic WD using the D -penicillamine challenge test (>1575 g/24 hours urine copper after 1 g penicillamine). Nevertheless, with regard to its low sensitivity and unsatisfactory diagnostic accuracy [5], it may have no advantage to urine copper excretion combined with measurement of serum ceruloplasmin for the diagnosis of WD [6]. On the basis of potential role of copper in AD, implication of penicillamine in AD patients has been tested in a randomized controlled clinical trial [7]. However, they did not find significant differences in AD progression between D -penicillamine and placebo groups. Moreover, they emphasized that whenever changes are observed, the D -penicillamine group showed a worse evolution, which highlights the toxic effect of iatrogenic copper intoxication. In contrast to the previous hypothesis, in 1961, the clinical neurologist Gerrit Schouwink postulated that the induction of a negative copper balance via halting intestinal copper absorption would be a rational strategy in treating copper intoxication in WD. However, the results have only been published in Dutch and remained unknown for years until TUH, noted the importance of the scientific comparative study by Schouwink and reported the efficacy of zinc therapy in WD [8]. Now, the treatment of symptomatic Wilson’s disease is no longer advised to aim at ‘decoppering’, the removal of accumulated copper, but at the normalization of the free copper concentration in blood, to reverse the copper poisoning [3]. Thus, as a consequence of this underreporting, for years patients have been deprived of an effective and safe treatment.
A. Avan and T.U. Hoogenraad / Zinc and Copper in Alzheimer’s Disease
ZINC THERAPY IN COPPER INTOXICATION Increased unbound or loosely-bound copper in serum is toxic and may induce neurodegeneration through oxidation and generation of free radicals [9]. Thus, a raised level of urinary and serum free copper are used as diagnostic tools. Taking the data from Schouwink’s experience, along with some further investigations that were performed in the Netherlands, there have been enough evidence to advocate zinc monotherapy as a safe and effective treatment of free copper intoxication (discussed in [10]). Zinc induces the production of intestinal metallothioneins, which will lead to increased excretion of free copper via the stool. Thus, TUH [3, 10] proposed zinc, which benefits efficacy, safety, and affordability, as initial treatment for copper toxicosis in WD. Serum concentration of copper and zinc are tightly intertwined, and an increase in the copper:zinc ratio in the elderly usually reflects an inflammatory response (reviewed in [11]). An increased ratio might drive systemic signals that resume maintenance and repair, whereas, a decreased ratio would be suggestive of promoting signals that regulate cellular proliferation and growth [11]. In summary, conscientious analytic cumulating of the available evidence has led to the hypothesis that free copper toxicosis does catalyze formation of amyloid in plaques and oxidative stress causing neurodegeneration in AD [9]. Although our knowledge of copper in AD is scarce and diverse (reviewed in [12]), in vitro and in vivo as well as recent genetic data [13], along with meta-analyses [14], sustain a systemic deregulation of copper in AD. Dyshemostasis in metals suggests a zinc-dependent immune response to the gradual development of aberrant metal hemostasis, oxidative stresses, and inflammation. An increase in zinc levels provokes metallothionein expression, which is a reactive response to neuronal damage, increased inflammation, and increased oxidative stress (discussed in [15]).
ever, the impact of this study would have been much improved if they had followed the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) guideline for systematic review and metaanalysis [16]. Thus, on the basis of available evidence, we echo the hypothesis that free copper toxicosis may play a causal role in age-related AD, and zinc therapy can be a rational causal treatment. A randomized controlled clinical trial testing a definite hypothesis is needed before conclusions can be drawn about the value of zinc supplements in the treatment of AD. DISCLOSURE STATEMENT Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/15-0186r1). REFERENCES [1]
[2]
[3]
[4]
[5]
[6]
[7]
[8] [9]
CONCLUSION We believe studies on zinc and copper may result in a breakthrough in the management of AD. The authors [1] cautiously indicated that serum zinc was significantly decreased in AD patients compared with healthy controls. This finding, despite the limitations acknowledged in their manuscript, may indeed support the metal hypothesis in the etiology of AD. How-
91
[10] [11]
[12]
Ventriglia M, Brewer GJ, Simonelli I, Mariani S, Siotto M, Bucossi S, Squitti R (2015) Zinc in Alzheimer’s disease: A meta-analysis of serum, plasma, and cerebrospinal fluid studies. J Alzheimers Dis 46, doi: 10.3233/JAD-141296 Hoogenraad TU (2011) Paradigm shift in treatment of Alzheimer’s disease: Zinc therapy now a conscientious choice for care of individual patients. Int J Alzheimers Dis 2011, 492686. Hoogenraad TU (2006) Paradigm shift in treatment of Wilson’s disease: Zinc therapy now treatment of choice. Brain Dev 28, 141-146. Bertrand E, Lewandowska E, Szpak GM, Hoogenraad T, Blaauwgers HG, Czlonkowska A, Dymecki J (2001) Neuropathological analysis of pathological forms of astroglia in Wilson’s disease. Folia Neuropathol 39, 73-79. Nicastro E, Ranucci G, Vajro P, Vegnente A, Iorio R (2010) Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology 52, 1948-1956. Schilsky ML (2007) Non-invasive testing for Wilson disease: Revisiting the d-penicillamine challenge test. J Hepatol 47, 172-173. Squitti R, Rossini PM, Cassetta E, Moffa F, Pasqualetti P, Cortesi M, Colloca A, Rossi L, Finazzi-Agro A (2002) dpenicillamine reduces serum oxidative stress in Alzheimer’s disease patients. Eur J Clin Invest 32, 51-59. Hoogenraad TU, Van den Hamer CJ, Koevoet R, Korver EG (1978) Oral zinc in Wilson’s disease. Lancet 2, 1262. Atwood CS, Huang X, Khatri A, Scarpa RC, Kim YS, Moir RD, Tanzi RE, Roher AE, Bush AI (2000) Copper catalyzed oxidation of Alzheimer Abeta. Cell Mol Biol (Noisy -legrand) 46, 777-783. Hoogenraad TU (1996) Wilson’s disease. In: Major Problems in Neurology Series. Vol. 30, W B Saunders. Malavolta M, Piacenza F, Basso A, Giacconi R, Costarelli L, Mocchegiani E (2015) Serum copper to zinc ratio: Relationship with aging and health status. Mech Ageing Dev. Pal A, Siotto M, Prasad R, Squitti R (2015) Towards a unified vision of copper involvement in Alzheimer’s disease: A review connecting basic, experimental, and clinical research. J Alzheimers Dis 44, 343-354.
92 [13]
[14]
A. Avan and T.U. Hoogenraad / Zinc and Copper in Alzheimer’s Disease Squitti R, Polimanti R, Siotto M, Bucossi S, Ventriglia M, Mariani S, Vernieri F, Scrascia F, Trotta L, Rossini PM (2013) ATP7B variants as modulators of copper dyshomeostasis in Alzheimer’s disease. Neuromolecular Med 15, 515-522. Squitti R, Simonelli I, Ventriglia M, Siotto M, Pasqualetti P, Rembach A, Doecke J, Bush AI (2014) Meta-analysis of serum non-ceruloplasmin copper in Alzheimer’s disease. J Alzheimers Dis 38, 809-822.
[15] [16]
Aschner M, West AK (2005) The role of MT in neurological disorders. J Alzheimers Dis 8, 139-145. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP (2007) Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. BMJ 335, 806-808.
