Metals and neurodegenerative diseases. A systematic review

Environmental Research 159 (2017) 82–94

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Metals and neurodegenerative diseases. A systematic review a,1

a,1

a

MARK b

Calogero Edoardo Cicero , Giovanni Mostile , Rosario Vasta , Venerando Rapisarda , ⁎ Salvatore Santo Signorellib, Margherita Ferrantea, Mario Zappiaa, Alessandra Nicolettia, a b

Department of Medical, Surgical Sciences and Advanced Technologies “G. F. Ingrassia”, University of Catania, Catania, Italy Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy

A R T I C L E I N F O

A B S T R A C T

Keywords: Metals Neurodegenerative diseases Systematic review

Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical presentation such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease (AD) and Parkinson's disease (PD). Genetic mutations have a known causative role, but the majority of cases are likely to be probably caused by a complex gene-environment interaction. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies and it is likely that each metal could be toxic through specific pathways. The possible pathogenic role of different metals has been supported by some epidemiological evidences coming from occupational and ecological studies. In order to assess the possible association between metals and neurodegenerative disorders, several case-control studies have also been carried out evaluating the metals concentration in different biological specimens such as blood/serum/plasma, cerebrospinal fluid (CSF), nail and hair, often reporting conflicting results. This review provides an overview of our current knowledge on the possible association between metals and ALS, AD and PD as main neurodegenerative disorders.

1. Introduction Neurodegenerative diseases are a group of neurological conditions characterized by a progressive and often untreatable clinical course. Genetic mutations have a known causative role but the large majority of cases has a multifactorial aetiology due to interactions between genotype, lifestyle and environmental factors. Among environmental risk factors, metals are gaining increasing attention because a larger percentage of population is exposed to industrial and chemical pollution through food, air and water (Kwok, 2010). Several metals are necessary to many physiological functions and their homeostasis is strictly regulated as their accumulation or their deficiency leads to human diseases (Fraga, 2005). The exact mechanism by which metals induce toxicity is not fully understood yet and it is likely that each metal could be toxic through specific pathways. Of particular importance, oxidative stress and neurodegeneration have been reported as consequences of toxic exposures to essential metals, along with dyshomeostasis in essential metal metabolism (Farina et al., 2013). Brain cells have several mechanisms that protect them from oxidative stress such as the glutathione system,

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1

thioredoxin/peroxiredoxin system, superoxide dismutases, and catalase (Baxter and Hardingham, 2016). An imbalance due to higher levels of oxidant factors or reduced levels of the antioxidant systems leads to cell death (Circu and Aw, 2010). It has been demonstrated that an increased production of superoxide and nitric oxide can be catalysed by Fenton reactions involving Iron (Fe), one of the redox active metals, after an imbalance in the cell redox system has led to increased superoxide levels (Jomova et al., 2010). Through the production of Reactive Oxygen Species (ROS) and the interaction with the cell signalling pathways, metals may induce DNA damage and lead to apoptosis (Valko et al., 2005). Moreover also epigenetic factors may play a role in the development of neurodegenerative diseases. DNA modifications, including DNA-bound histones, DNA methylation, and chromatin remodelling, may depend from environmental clues, such as lifestyle, diet and toxin exposure. Metals may also interact with genes expression increasing the production of genes associated with neurodegenerative diseases (Kwok, 2010; Lahiri et al., 2009). To date, however, available evidences of a possible causative or concausal role of metals in neurodegenerative diseases involving humans and including Amyotrophic Lateral Sclerosis (ALS), Alzheimer

Correspondence to: Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", Università degli Studi di Catania, Via Santa Sofia 79, 95123, Catania, Italy. E-mail address: [email protected] (A. Nicoletti). These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.envres.2017.07.048 Received 4 July 2017; Received in revised form 26 July 2017; Accepted 28 July 2017 0013-9351/ © 2017 Published by Elsevier Inc.

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Spain to assess the trend and geographical pattern in motor neuron diseases (MND) incidence in Spain and the possible air lead levels effect on this pathology. The authors reported a higher mortality rates among people over 65 years, in Northern provinces with a significant association of MND mortality with higher air lead levels (CC = 0.457, p = 0.01) suggesting an important role of environmental exposures (Santurtún et al., 2016). On the bases of these evidences, several case-control studies have evaluated the lead concentration in biological specimens. An increased lead concentration in blood and CSF among ALS cases with respect to healthy controls has been reported by seven case-control studies (four in blood samples and three in CSF samples) (Bocca et al., 2015; Conradi et al., 1976; Fang et al., 2010; Garzillo et al., 2014; Kamel et al., 2002; Roos et al., 2013; Vinceti et al., 2017) while no increased blood lead level was reported only in one study (Vinceti et al., 1997). No differences in lead concentration have been reported in urine, hair and toenail samples (Bergomi et al., 2002; Bocca et al., 2015) (Table 1).

disease (AD) and Parkinson's disease (PD) are still limited. The aim of the present study is to provide an updated summary of the literature evidences on the possible relationship between metals and ALS, AD and PD representing the main neurodegenerative disorders. 2. Materials and methods 2.1. Literature search A systematic MEDLINE search was conducted by a medical investigator without past time or language restriction, to identify published observational, case-control studies dealing with the association between metals and neurodegenerative disorders. Combined text words and Medical Subject Headings (MeSH) terminology were used. Specifically, to detect available study evaluating blood/serum/plasma metals in ALS, AD and PD, search key words including metals together with boolean operators were entered in Pubmed as search strategy. Titles were scanned for relevance, identifying papers requiring further consideration. For the systematic research, a period up to January 2017 was considered.

3.1.2. ALS and selenium Excessive exposure to the metalloid selenium (Se), a trace element with both toxicological and nutritional properties, has been implicated in the aetiology of ALS. Se, in both organic and inorganic compounds, has been proved to play a contributory role in several pathogenetic mechanisms involved in the neurotoxic process (Trojsi et al., 2013). Several veterinary observations have demonstrated a specific toxicity of Se to motor neurons in swine and cattle. Accidental Se intoxication, in fact, determined a selective damage to motor neurons in swine and several motor symptoms, such as walking disturbances or paralysis and death from respiratory failure, have also been recorded in cattle (Casteignau et al., 2006; Davidson-York et al., 1999; Maag et al., 1960). Two epidemiological surveys have reported an increased risk of ALS in populations resident in seleniferous areas suggesting a probable causal link between Se exposure and ALS risk. In particular, a first cluster of ALS has been highlighted by a study that reported four ALS cases in a small county of about 4000 inhabitants in the west-central South Dakota, a region characterized by high incidence of selenosis in farm animals (Kilness and Hichberg, 1977). A further epidemiological observation concerning the possible association between high Se environmental levels and an increased incidence of ALS reported was performed in 1996 in the Northern Italy municipality of Reggio Emilia, where high levels of Se were detected in the waters of the two wells, which were the source of municipal tap water from 1972 to 1988 (Vinceti et al., 1996). The authors examined the 9 years' incidence of ALS in a cohort of 5182 residents who drank for at least five years the high-Se tap water and reported an increased ALS risk in this municipality (four newly diagnosed ALS cases, compared to the 0.64 expected ones) with a standardized incidence ratio of 4.22 (Vinceti et al., 1996). The same authors also reported an excess mortality from Parkinson's disease and ALS during 1986–1997 among residents of the same area exposed to drinking water with a high content of inorganic selenium (Vinceti et al., 2000). Nevertheless, despite these epidemiological evidences, only one study recorded a higher concentration of selenium in CSF of ALS cases with respect to controls and another has reported a high selenium concentration in blood samples (Nagata et al., 1985; Vinceti et al., 2013). Conversely, other three studies have reported a similar selenium level in toenail, CSF and blood specimens (Bergomi et al., 2002; Roos et al., 2013; Vinceti et al., 1997). while two (Moriwaka et al., 1993; Peters et al., 2016) reported reduced selenium blood levels (Table 1).

3. Results 3.1. Metals and Amyotrophic Lateral Sclerosis (ALS) ALS is a rapidly progressive, neurodegenerative disorder that mostly affects motor neurons. In Europe, the incidence of ALS is about 2–3 cases per 100,000 (Al-Chalabi and Hardiman, 2013), the prevalence is 5.4 per 100,000 (Belbasis et al., 2016). About 10% of cases are genetic; in the remaining cases aetiology is thought to be multifactorial, given by the concomitance of a genetic predisposition and environmental factors (Al-Chalabi and Hardiman, 2013). A handful of factors have been proposed to be associated with ALS; however, the only established risk factors to date are older age, male sex and a family history of ALS (Belbasis et al., 2016). The potential role of metals into the molecular mechanisms that lead to the degeneration of motor neurons has been widely explored. Evidences on the possible relationship between metals and ALS mainly arise from both occupational and ecological studies as well as from case-control studies in which metals concentration has been evaluated in different biological specimens such as cerebrospinal fluid (CSF), blood, hair, nail and urine. The majority of these evidences concerns the potential role of lead, selenium, iron, manganese and mercury (Table 1). 3.1.1. ALS and lead That lead (Pb) can play a role in ALS pathogenesis is a long-standing hypothesis since many ALS and ALS-like cases with antecedent occupational exposure to lead have been reported in literature (Bachmeyer et al., 2012; Boothby et al., 1974; Campbell et al., 1970; Fluri et al., 2007; Livesley and Sissons, 1968). The involvement of lead in sporadic ALS is biologically plausible due to its possible role in oxidative stress, excitotoxicity and mitochondrial dysfunction (Kamel et al., 2005). The possible association between lead exposure and ALS has been consistently supported by several retrospective case-control studies that have investigated the possible past occupational exposure to lead generally using standardized questionnaires (Chancellor et al., 1993; Deapen and Henderson, 1986; Felmus et al., 1976; Gunnarsson et al., 1992; Pierce-Ruhland and Patten, 1981; Strickland et al., 1996). This association was also reported in a recent meta-analysis including nine case-control studies specifically addressing the risk associated with occupational exposure to lead. According to Wang et al, the risk of developing ALS among individuals with a history of exposure to lead was almost doubled with a pooled odds ratio of 1.81 (95% CI 1.39–2.36) (Wang et al., 2014). Furthermore, an ecological study has been recently carried out in

3.1.3. ALS and manganese Manganese (Mn) is necessary for many metalloenzymes; moreover, it acts as a cofactor in several enzymatic reactions (Klaassen, 2013). Manganese crosses barrier systems at the choroid plexus and accumulates in the central nervous system, with a longer half-life in nervous tissue. Chronic-manganese exposition can occur in many occupational 83

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Table 1 Associations between specific metals levels in biological samples and ALS. Evidences from case-control studies. Authors

Years

Sample

Cases

Controls

Se

Pb

Mg

Fe

Cu

Al

As

Cd

Co

Zn

V

U

Cr

Hg

Mn

Bergomi Bocca Bocca Bocca Conradi Fang Garzillo Hozumi Kamel Kapaki Moriwaka Nagata Peters Roos Roos Roos Roos Vinceti Vinceti Vinceti

2002 2015 2015 2015 1976 2010 2014 2011 2002 1997 1993 1985 2016 2013 2012 2012 2013 1997 2017 2013

N H U B CSF B B CSF B CSF B B B CSF CSF B B B CSF CSF

22 34 34 34 12 184 34 52 107 28 21 40 163 17 17 17 15 16 38 38

40 30 30 30 28 194 25 15 41 38 36 25 229 10 10 19 9 39 38 38

0 / / / / / / / / / – + – 0 / / 0 0 / +

0 0 0 + + + + / + / / / / + / / 0 0 + /

/ / / / / / / + / 0 / / / 0 / / 0 / / /

0 / / / / / / + / / / 0 / 0 / / 0 / / /

0 / / / / / / + / – / / + + / / 0 / / /

0 – 0 + / / 0 / / / / / / + / / 0 / / /

/ / / / / / / / / / / / / 0 / / 0 / / /

0 0 0 0 / / / / / / / / / + / / 0 + – /

0 / / / / / / / / / / / / + / / 0 / / /

0 / / / / / / + / 0 / 0 – + / / 0 / / /

/ / / / / / / / / / / / / + / / 0 / / /

/ / / / / / / / / / / / / + / / 0 / / /

0 / / / / / / / / / / / / / / / 0 / / /

/ 0 0 0 / / / / / / – / / 0 / / + / – /

0 – 0 0 / / 0 0 / + / – 0 + + 0 0 / / /

B = blood; CSF = cerebrospinal fluid; U = Urine; H = Hair; N = Nail; + = Positive association; - = Inverse Association; 0 = No Association; / = Not evaluated. Se = Selenium; Pb = Lead; Mg = Magnesium; Fe = Iron; Cu = Copper; Al = Aluminium; As = Arsenic; Cd = Cadmium; Co = Cobalt; Zn = Zinc; V = Vanadium; U = Uranium; Cr = Chromium; Hg = Mercury; Mn = Manganese.

3.1.5. ALS and mercury Methylmercury (MeHg) is the most important organic mercury (Hg) compound and diet, through fish and derivatives, represents its dominant source, even if occupational exposure is also considerable. In vitro and in vivo studies seem to suggest that mercury exposure might be implicated in the aetiology of ALS (Arvidson, 1992; Chuu et al., 2007) and this hypothesis has also been supported by some case reports describing syndrome resembling ALS after intense exposure to elemental mercury (Adams et al., 1983; Barber, 1978; Schwarz et al., 1996). Furthermore a cluster of ALS has been identified in a small Wisconsin community, characterized by large consumption of freshly caught Lake Michigan fish, containing high levels of mercury (Sienko et al., 1990). However four retrospective case-control studies have evaluated mercury concentration in different biological specimens reporting no association (Bocca et al., 2015), a significant lower concentration of mercury among ALS cases (Moriwaka et al., 1993; Vinceti et al., 2017) or the opposite (Roos et al., 2013) as reported in Table 1.

settings, such as manganese mines and smelters, in factories making batteries, iron-alloys, glass, in case of exposition to pesticides containing manganese. It causes a complex syndrome including parkinsonism (manganism, see below) (Klaassen, 2013). However, up to date case-control studies or occupational cohorts have not reported univocal evidences of a possible association between manganese exposure and ALS (Sjögren et al., 1996). Nine case-control studies (Bergomi et al., 2002; Bocca et al., 2015; Garzillo et al., 2014; Hozumi et al., 2011; Kapaki et al., 1997; Nagata et al., 1985; Peters et al., 2016; Roos et al., 2012, 2013) have evaluated the manganese concentration in different biological specimens overall reporting negative results except for two studies that demonstrated a lower manganese concentration respectively in blood and hair samples of ALS patients (Bocca et al., 2015; Nagata et al., 1985). On the other hand, only two studies have reported a significantly higher concentration of manganese in CSF of ALS patients with respect to healthy controls (Kapaki et al., 1997; Roos et al., 2013, 2012) (Table 1).

3.1.6. ALS and other metals Some case-control studies have also evaluated the possible role of other metals such as copper (Cu), aluminum (Al), arsenic (As), cadmium (Cd), cobalt (Co), zinc (Zn), vanadium (Va), magnesium (Mg), uranium (U) and chromium (Cr) generally reporting conflicting results as shown in Table 1. In particular three out five studies have reported an increased level of copper in ALS cases (two in CSF and one blood sample) (Hozumi et al., 2011; Peters et al., 2016; Roos et al., 2013) and two out of six studies have also reported an increased CSF concentration of zinc (Hozumi et al., 2011; Roos et al., 2013). Some evidences of possible association have also been found for cadmium (Roos et al., 2013; Vinceti et al., 1997) while for the other metals a lack of association has often been reported (Table 1).

3.1.4. ALS and iron Iron serves as a cofactor for regulatory enzymes in the electron transport chain in the mitochondria. Brain iron content increases with age, and iron accumulation has been noted in other neurodegenerative disorders (Dusek et al., 2015). Despite the reported association between iron and neurodegenerative disorders only few studies have evaluated the possible association between iron and ALS. In particular, out of four case-control studies that have evaluated the possible relationship between iron and ALS assessing the iron concentration in biological specimens, only one has reported a higher CSF iron concentration among ALS patients (Hozumi et al., 2011), while no association has been reported in blood, nail and CSF sample in three studies (Bergomi et al., 2002; Nagata et al., 1985; Roos et al., 2013) (Table 1). On the other hand, different studies have evaluated the possible association between serum ferritin level and ALS. Ferritin is an iron storage protein associated with response to oxidation stress and it is essential for the maintenance of iron homeostasis. A recent meta-analysis including 6 case-control studies reported a positive association between elevated serum ferritin levels and ALS with a pooled mean difference between all ALS patients and healthy controls of 69.05 μg/L (95% CI: 52.56–85.54; p < 0.00001) (Hu et al., 2016).

3.2. Metals and Alzheimer’s disease (AD) AD is a neurodegenerative disorder characterized by progressive loss of memory and cognitive functions that leads to severe impairment in the activities of daily living. According to the World Alzheimer Report in 2015 46.8 million of people were suffering from this condition and numbers will raise to 74.7 millions in 2030 (“World Alzheimer Report, 2015: The Global Impact of Dementia Alzheimer’s Disease 84

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pro-oxidant agent leading to neurodegeneration, melatonin may instead exert as counterpart an antioxidant action by increasing the mRNA levels of the antioxidant enzymes in presence of aluminum (García et al., 2009, 2010), improving learning and spatial memory performances in aluminum-exposed transgenic mice (Di Paolo et al., 2014). In fact there is evidence of higher antioxidant activity in the brains of rats exposed to Al and melatonin (Esparza et al., 2003, 2005). Interaction with other metalloids exposition, specifically silicon, may result also in a protective effect limiting oral aluminum absorption in animal models (Bellés et al., 1998; Domingo et al., 2011). A possible association between aluminum exposition and neurodegeneration in humans has been suggested by analyzing metal concentration in drinking water of a specific selected area, showing a high rate of AD cases among elderly people exposed to high aluminum concentration (Ferreira et al., 2009). Human studies generally showed higher levels of aluminum concentration in the blood of patients (Basun et al., 1991; Baum et al., 2010; González-Domínguez et al., 2014; Smorgon et al., 2004; Zapatero et al., 1995) with the exception of two studies (Alimonti et al., 2007; Bocca et al., 2005). Lower concentrations have been demonstrated also in both hair (Kobayashi et al., 1989; Koseoglu et al., 2017) and bone (O’Mahony et al., 1995). CSF and nail concentration studies were inconclusive (Basun et al., 1991; Koseoglu et al., 2017) (Table 2).

International”). No effective treatment is available to stop the progression of the disease that has its pathological hallmark in the progressive deposition in brain tissues of beta-amyloid plaques and neurofibrillary tangles. Pathogenesis is still unknown but it has been speculated that metal dyshomeostasis may play a role in accelerating the formation of beta amyloid in the brain, as part of the “amyloid hypothesis” (Mattson, 2004). Association between environmental risk factors and dementia has been recently reviewed (Killin et al., 2016) showing that air pollution and metals have a part in the pathological mechanisms that lead to AD. 3.2.1. AD and lead Lead is a toxic heavy metal. Its effect is mediated by the production of reactive oxygen species that cause cellular damage by increasing oxidative processes and depleting the cellular antioxidants deposits (Jomova and Valko, 2011). It is responsible for poor cognitive performances in cohorts of persons exposed to the pollutant (Dorsey et al., 2006; Khalil et al., 2009), and a possible association between blood lead levels and AD has been evaluated in several case control studies that however found no significant increase in concentration (Alimonti et al., 2007; Basun et al., 1991; Bocca et al., 2005; Gerhardsson et al., 2008; González-Domínguez et al., 2014; Paglia et al., 2016; Park et al., 2014) except for one (Giacoppo et al., 2014). Two studies on CSF gave discordant result: one (Basun et al., 1991) found no difference and another (Gerhardsson et al., 2008) found reduced concentration of lead. Regarding studies on other tissues, one study (Koseoglu et al., 2017) found reduced lead concentration in the hair and no difference in nails samples (Table 2). In fact, a systematic review of 2007 showed no significant increased risk in professional exposure to lead and dementia (Santibanez et al., 2007).

3.2.4. AD and iron Iron has been found in higher levels in AD brains (Smith et al., 2010) and is responsible for oxidative stress and increased deposition of amyloid plaques (Jomova and Valko, 2011). Two epidemiological studies found a relationship between higher levels of soil iron and AD: Emard et al. (1994) found an increase in diagnosis of AD in subjects born from iron rich soil while Shen et al. (2014) found increased AD related mortality in China’s regions with high levels of soil iron. Out of 22 studies that evaluated iron levels in both cases and controls, only eight found reduced concentration in blood of AD patients (Alimonti et al., 2007; Basun et al., 1991; Baum et al., 2010; Bocca et al., 2005; Crespo et al., 2014; Faux et al., 2014; Vural et al., 2010; Wang et al., 2015), while 12 found no differences (Farrar et al., 1990; Gerhardsson et al., 2008; Giambattistelli et al., 2012; Goldust et al., 2013; GonzálezDomínguez et al., 2014; Koç et al., 2015; Molaschi et al., 1996; Molina et al., 1998; Paglia et al., 2016; Squitti et al., 2002, 2007c; Torsdottir et al., 2011) and two increased concentrations (Ozcankaya and Delibas, 2002; Singh et al., 2014). CSF studies were inconclusive (Gerhardsson et al., 2008; Hershey et al., 1983; Hozumi et al., 2011; Molina et al., 1998). Studies on nails and hair were inconclusive too (Koç et al., 2015; Vance et al., 1988), except for one (Koseoglu et al., 2017) that found reduced iron levels in both hair and nails (Table 2).

3.2.2. AD and mercury Mercury may play a role as a cofactor in the pathogenesis of AD, as evidences from studies in vitro and animal models showed (Mutter et al., 2010). Its mechanism of action probably linked to an increased production and reduced destruction of β-amyloid. Occupational studies in exposed workers showed an inverse relation between mercury excretion and cognitive functions (Mutter et al., 2010). To date, four case control studies that performed a blood evaluation of Hg found higher levels in AD than controls (Basun et al., 1991; Bocca et al., 2005; Gerhardsson et al., 2008; Hock et al., 1998), while the other studies either found lower concentrations (Paglia et al., 2016) or no difference (Alimonti et al., 2007; Fung et al., 1995; Giacoppo et al., 2014; Park et al., 2014). Only two groups have investigated Hg in CSF and found no difference in concentration (Basun et al., 1991; Gerhardsson et al., 2008). Nails concentration of Hg has also been found markedly reduced in two studies (Koseoglu et al., 2017; Vance et al., 1988). The studies on hair found inconsistent results (Koseoglu et al., 2017; Vance et al., 1988) (Table 2).

3.2.5. AD and copper Like iron, high levels of copper are thought to be responsible for the production of ROS in brain tissue and the induction of neurodegeneration (Jomova and Valko, 2011). Copper interacts with APP and promotes the production of amyloid plaques and neurofibrillary tangles (Squitti et al., 2014a). The same epidemiologic studies that hypothesized a relation between higher iron soil levels and AD reported conflicting results for copper with Emard et al. (1994) discarding the connection between higher copper levels and AD diagnosis, and Shen et al. (2014) showing a positive correlation. Evaluation of copper levels in blood has produced conflicting results: 19 studies (Alimonti et al., 2007; Al-khateeb et al., 2014; Basun et al., 1991; Baum et al., 2010; Bocca et al., 2005; Brewer et al., 2010a; Gerhardsson et al., 2008; González-Domínguez et al., 2014; Jeandel et al., 1989; Kapaki et al., 1989; Koç et al., 2015; Molaschi et al., 1996; Molina et al., 1998; Ozcankaya and Delibas, 2002; Paglia et al., 2016; Rembach et al., 2013; Sedighi et al., 2006; Shore et al., 1984; Snaedal et al., 1998) found no differences in blood while 17 found a higher level of this metal (Agarwal et al., 2008; Alsadany et al., 2013; Gonzalez et al., 1999;

3.2.3. AD and aluminum The relation between aluminum and AD is well known since the earliest anatomopathological studies (Crapper et al., 1973). A recent systematic review has showed aluminum as the most studied metal in epidemiological studies and even if results are controversial the larger environmental studies have showed an association between high levels of exposure and risk of AD (Killin et al., 2016). Aluminum is probably involved in AD pathogenesis through the promotion of amyloid precursor protein production (APP) and thus increasing beta amyloid deposits in the brain (Walton and Wang, 2009). However, in AD animal models aluminum exposition through the diet did not determine relevant changes in heavy metals tissues concentration as compared to wild-type mice (Gómez et al., 2008). Even if not relevant interaction with the amyloidogenic pathway has been detected, an aluminum-induced impairment in learning and memory performances has been instead hypothesized (Ribes et al., 2008). While aluminum may act as a 85

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Table 2 Associations between specific metals levels in biological samples and AD. Evidences from case-control studies. Authors

Year

Sample

Cases

Controls

Ni

Fe

Cu

Se

Zn

Mn

Cr

Hg

Al

Pb

Agarwal Alimonti Al-khateeb Alsadany Barbagallo Basun Basun Baum Bocca Borella Brewer Brewer Brewer Cardoso Cardoso Cardoso Ceballos-Picot Crespo Farrar Faux Fung Gerhardsson Gerhardsson Giacoppo Giambattistelli Goldust Gonzalez Gonzàlez-Dominguez Gustaw-Rothenberg Hershey Hock Hozumi Jeandel Kapaki Kapaki Kobayashi Koç Koç Koseoglu Koseoglu Krishnan López Meseguer Meseguer Molaschi Molina Molina O'Mahony Ozcankaya Paglia Park Park Rembach Sedighi Sevim Shore Shore Singh Smorgon Snaedal Squitti Squitti Squitti Squitti Squitti Squitti Squitti Squitti Subhash Subhash Torsdottir Vance Vance Vural

2008 2007 2014 2013 2011 1991 1991 2010 2005 1990 2010 2010 2010 2010 2010 2014 1996 2014 1990 2014 1995 2008 2008 2014 2012 2013 1999 2014 2009 1983 1998 2011 1989 1989 1989 1989 2015 2015 2017 2017 2014 2013 1999 1999 1996 1998 1998 1995 2002 2016 2014 2014 2013 2006 2007 1984 1984 2014 2004 1998 2005 2006 2006 2007 2008 2013 2002 2007 1991 1991 2011 1988 1988 2009

B B B B B B CSF B B B U B B B N B B B B B B B CSF B B B B B B CSF B CSF B B CSF H B H H N B B B CSF B B CSF BONE B B B B B B B B H B B B B B CSF B B B B B CSF B B N H B

50 53 52 25 36 24 24 44 60 n.a. 29 29 28 28 28 28 40 116 10 211 9 173 173 15 107 50 51 30 30 33 33 21 55 9 9 35 45 45 62 62 30 36 27 27 31 26 26 7 27 34 89 89 152 50 98 10 10 100 8 44 47 28 28 25 25 399 79 51 40 40 41 63 63 47

50 124 50 25 65 n.a. n.a. 41 44 n.a. 29 29 29 29 29 29 34 84 15 768 9 54 54 10 52 50 40 30 29 20 65 15 24 28 28 71 33 33 60 60 40 33 34 34 421 28 28 19 25 40 118 118 716 50 78 10 10 100 11 44 44 25 25 25 25 303 76 53 20 20 41 117 117 43

/ 0 / / / 0 / / 0 / / / / / / / / / / / / 0 0 / / / / / / / / / / / / / / / / / / / / / / / / / / 0 / / / / / / / / / / / / / / / / / / / / / / / /

/ – / / / – / – – / / / / / / / / – 0 – / 0 0 / 0 0 / 0 / 0 / 0 / / / / 0 0 – – / / / / 0 0 0 / + 0 / / / / / / / + / / / / / / / / 0 0 / / 0 0 0 /

+ 0 0 + / 0 + 0 0 / / / 0 / / / / / / / / 0 0 – / / + 0 / 0 / 0 0 0 0 / 0 – – – / + / / 0 0 0 / 0 0 / + 0 0 + 0 0 + + 0 + + 0 + + + + + / / / / / /

/ / / / / + / 0 / / / / / – – – + / / / 0 – 0 – / / / 0 / / / / 0 / / / 0 – / / 0 / 0 0 / / / / / 0 / / / / / / / / – / / / / / / / / / / / / 0 0 /

/ – / / / 0 / – – / 0 – / / / / / / / / / 0 0 – / / 0 – / + / 0 – 0 0 / 0 – 0 – / / / / 0 0 – / 0 0 / / / / – 0 0 / / / / / / / / / / / / / / + + /

/ 0 / / / – / 0 0 / / / / / / / / / / / / + – / / / / – / / / 0 / / / / – + – – / / / / / 0 0 / / – / / / / / / / / / / / / / / / / / / / / / / / –

/ 0 / / / 0 / 0 0 / / / / / / / / / / / / / / / / / / 0 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / – / / / / / / / / / / / / 0 0 /

/ 0 / / / + 0 / + / / / / / / / / / / / 0 + 0 0 / / / / / / + / / / / / / / – – / / / / / / / / / – 0 / / / / / / / / / / / / / / / / / / / / – 0 /

/ 0 / / / + 0 + – / / / / / / / / / / / / / / / / / / + / / / / / / / – / / – 0 / / / / / / / – / / / / / / / / / / + / / / / / / / / / / / / / / /

/ 0 / / / 0 0 / 0 / / / / / / / / / / / / 0 – – / / / 0 / / / / / / / / / / – 0 / / / / / / / / / 0 0 / / / / / / / / / / / / / / / / / / / / / / /

86

Mg / 0 / / 0 0 0 / + – / / / / / / / / / / / 0 0 / / / / / 0 / / 0 / 0 0 – 0 0 0 0 / / / / / / / / / / / / / / / 0 0 – / / / / / / / / / / / / / / / / (continued

As

Cd

/ / / / / 0 / 0 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 0 / / / / / / / / / / / / / / / / / / / / 0 0 / on next

/ 0 / / / + – / + / / / / / / / / / / / / 0 0 / / / / 0 / / / / / / / / / / – – / / / / / / / / / / 0 / / / / / / / / / / / / / / / / / / / / / / / page)

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Table 2 (continued) Authors

Year

Sample

Cases

Controls

Ni

Fe

Cu

Se

Zn

Mn

Cr

Hg

Al

Pb

Mg

As

Cd

Vural Wang Zapatero Zappasodi

2010 2015 1995 2008

B B B B

50 83 17 54

50 83 189 20

/ / / /

– – / /

– + / +

– / / /

– 0 / /

/ / / /

/ / / /

/ / / /

/ / + /

/ / / /

– / / /

/ / / /

/ / / /

B = blood; CSF = cerebrospinal fluid; U = Urine; H = Hair; N = Nail; + = Positive association; - = Inverse Association; 0 = No Association; / = Not evaluated. Ni = Nickel; Fe = Iron; Cu = Copper; Se = Selenium; Zn = Zinc; Mn= Manganese; Cr = Chromium; Hg = Mercury; Al = Aluminum; Pb = Lead; Mg = Magnesium; As = Arsenic; Cd = Cadmium.

3.2.8. AD and manganese In pathological studies manganese, as part of the superoxide-dismutase (Mn-SOD) antioxidative stress enzyme, has been found associated with senile plaques (Maeda et al., 1997). A role of this metal in the activity of the arginase enzyme has been showed to inversely correlate with the free radical NO production in AD subjects (Vural et al., 2009). The cross-sectional study of Emard et al. (1994) found that in areas with higher Mn concentration more people with a diagnosis of AD were born. Mn concentration in serum samples of AD patients has been found reduced in five studies (Basun et al., 1991; González-Domínguez et al., 2014; Koç et al., 2015; Paglia et al., 2016; Vural et al., 2009) out of nine studies (Alimonti et al., 2007; Baum et al., 2010; Bocca et al., 2005; Molina et al., 1998). Only one study (Gerhardsson et al., 2008) found higher Mn levels. CSF studies reported either no differences (Hozumi et al., 2011; Molina et al., 1998) or reduced levels (Gerhardsson et al., 2008). Hair concentration was normal in one study (Koç et al., 2015) and reduced in both hair and nails in another (Koseoglu et al., 2017) (Table 2).

López et al., 2013; Park et al., 2014; Sevim et al., 2007; Singh et al., 2014; Smorgon et al., 2004; Squitti et al., 2007c; Squitti et al., 2007b; Squitti et al., 2013, 2008, 2006, 2005, 2002; Wang et al., 2015; Zappasodi et al., 2008). It is worth to mention that two studies found a lower level of serum copper in AD patients (Giacoppo et al., 2014; Vural et al., 2010) and two (Koç et al., 2015; Koseoglu et al., 2017) reported lower copper levels in nails and hair of AD subjects. CSF studies have been generally inconclusive (Gerhardsson et al., 2008; Hershey et al., 1983; Hozumi et al., 2011; Kapaki et al., 1989; Molina et al., 1998; Squitti et al., 2006) except for one (Basun et al., 1991) that found higher copper levels (Table 2).

3.2.6. AD and selenium Selenium has an important role in the oxidative stress defensive system of the brain as it is the active part of a group of antioxidants proteins known as selenoproteins that protect neurons and astrocytes (Steinbrenner and Sies, 2013). In a review on selenium and Alzheimer’s disease (Loef et al., 2011) two studies are reported that found a negative correlation between selenium levels in water and cognitive performances in two cohorts of elderly Chinese subjects (Emsley et al., 2000; Gao et al., 2007). Only six studies found reduced levels of selenium in blood of AD patients (Cardoso et al., 2010; Cardoso et al., 2014; Gerhardsson et al., 2008; Giacoppo et al., 2014; Smorgon et al., 2004; Vural et al., 2010) out of 16 studies. Two studies, however, reported higher Se levels in AD patients (Basun et al., 1991; Ceballos-Picot et al., 1996). CSF studies were inconclusive (Gerhardsson et al., 2008; Meseguer et al., 1999). Nails and hair studies found reduced levels of selenium (Cardoso et al., 2010; Koç et al., 2015) with one exception (Vance et al., 1988) (Table 2).

3.2.9. Other metals For arsenic some evidence comes from epidemiological studies that have found an association between higher soil levels and higher rates of AD in European countries (Dani, 2010) but no evidence has been drawn from measuring As in biological samples. Data on other metals (magnesium, nickel (Ni), chromium, cadmium) are inconclusive (see Table 2). 3.3. Metals and Parkinson’s disease (PD) PD is a neurological disorder pathologically characterized by the degeneration of the substantia nigra pars compacta and the Lewy body pathology, with dopamine deficiency within the basal ganglia leading to defects in motor controls (Kalia and Lang, 2015). Clinical features for the diagnosis are represented by the classic parkinsonian signs, including bradykinesia, muscular rigidity, rest tremor and postural instability, as indicated by the available diagnostic criteria (Hughes et al., 1992). Pathological mechanisms which subtend the disease are still poorly understood. The role of metals in such pathological processes has been hypothesized based on available observational studies evaluating occupational and environmental expositions as well as levels of metals in biological fluids using a case-control study design. Principal limits of these available observational studies are related to possible recall as well selection bias, which may lead difficult to estimate an outlined causal link (Hill, 1965). Principal evidences of a possible association between PD and single metals are listed below.

3.2.7. AD and zinc Zinc is a transition metal used in different biochemical pathways, however recently it has been demonstrated that beta amyloid plaques contain high level of zinc, and the subsequent removal of zinc from intracellular space may lead to microtubule disaggregation and neurofibrillary tangles formation (Craddock et al., 2012). Two environmental studies investigated the relation between zinc soil levels and AD: one found no correlation (Emard et al., 1994) the other found higher AD mortality in zinc-rich soil (Shen et al., 2014). Eleven case-control studies showed no significant differences when evaluating blood concentration of zinc in AD patients and controls (Basun et al., 1991; Gerhardsson et al., 2008; Gonzalez et al., 1999; Kapaki et al., 1989; Koç et al., 2015; Molaschi et al., 1996; Molina et al., 1998; Ozcankaya and Delibas, 2002; Paglia et al., 2016; Shore et al., 1984; Wang et al., 2015); nine found lower zinc levels in AD (Alimonti et al., 2007; Baum et al., 2010; Bocca et al., 2005; Brewer et al., 2010b; Giacoppo et al., 2014; González-Domínguez et al., 2014; Jeandel et al., 1989; Sevim et al., 2007; Vural et al., 2010). CSF studies reported generally no differences in concentration (Gerhardsson et al., 2008; Hozumi et al., 2011; Kapaki et al., 1989) except for two (Hershey et al., 1983; Molina et al., 1998) that respectively found lower and higher levels of zinc in CSF. Sampling of nails and hair led to conflicting results (Table 2).

3.3.1. PD and iron PD is associated with extensive involvement of iron, with most extensive deposition in substantia nigra and lateral globus pallidus, as well as in dopaminergic neurons. The sources of increased iron should be searched in one or all of the following: homeostatic dysregulation; dysregulation of molecules involved in the intra- and extracellular distribution of iron; aging (Jellinger, 2013). Data from observational studies on occupational and environmental 87

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iron levels in hair were also described in PD as compared to controls (Bocca et al., 2006).

exposition are not uniform. In a population-based case-control study evaluating worksite conditions using a standardized questionnaire, a not significant association was detected, also after stratifying for time of exposition (Gorell et al., 1997). In the same population, stratified results for PD family history revealed also no significant association, even though higher for patients with a positive compared to negative family history (Lai et al., 2002; Rybicki et al., 1999). A third epidemiological study conducted in Quebec reported instead a significant increased risk for PD to be associated with occupational iron exposure, but an estimated odds ratio was provided for an overall occupational exposure to the three metals iron, manganese and aluminum (Lai et al., 2002; Zayed et al., 1990). Concerning data on case-controls studies on blood levels differences among PD patients versus controls, this topic has been discussed in a specific article (Mostile et al., 2017). Data on other biological fluids, including CSF and urine, or tissue, such as hair, are less reported. In CSF, a significant lower iron concentration has been detected in PD patients as compared to age-matched controls (Alimonti et al., 2007). Same results were obtained in a second work, with lower iron in CSF of PD subjects when compared to controls (Bocca et al., 2006), suggesting consistency of results. Differences in iron CSF levels between PD patients and controls with a borderline significant level were also detected (Forte et al., 2004). Other studies, however, did not confirm significant differences in CSF serum levels between patients and controls (Gazzaniga et al., 1992; Hozumi et al., 2011; Jiménez-Jiménez et al., 1998; Pall et al., 1987) (see Table 3). About data on iron levels on tissue samples such as hair, high levels of iron, lead, cadmium and aluminum were found in subjects with Parkinsonism and arthritis enrolled from Ulaanbaatar and other areas in Mongolia, probably induced by eating large amounts of sheep meat (Komatsu et al., 2011). However, opposite results with significant lower

3.3.2. PD and copper In PD, free copper has been implicated in oxidative stress mechanisms, alpha-synuclein oligomerization and Lewy body formation, as well as in GABA-A and NMDA neurotransmitters modulation. It may also influence iron content in the brain through ferroxidase ceruloplasmin activity (Montes et al., 2014). Evidences from studies on occupational and environmental exposition involve the same studies investigating also iron exposition, revealing, as compared to controls, a not significant adjusted OR of 1.55 (95%CI 0.87 – 2.77; p = 0.139) (Gorell et al., 1997), as well as not significant association also stratifying for confounding variables such as family history for PD (Lai et al., 2002; Rybicki et al., 1999). Concerning data on case-controls studies on copper blood level differences among PD patients versus controls, data are not exhaustive since eight different studies reported both significant positive (Ahmed and Santosh, 2010; Hegde et al., 2004; Kumudini et al., 2014; Squitti et al., 2007a) and negative (Bharucha et al., 2008; Forte et al., 2004; Younes-Mhenni et al., 2013; Zhao et al., 2013) associations, while other 12 studies reported no significant results (see Table 3). Data on CSF levels reported both high levels in PD as compared to controls (Boll et al., 2008; Hozumi et al., 2011; Pall et al., 1987), as well as no differences between groups (Alimonti et al., 2007; Bocca et al., 2006; Boll et al., 1999; Forte et al., 2004; Gazzaniga et al., 1992; Jiménez-Jiménez et al., 1998) (Table 3). 3.3.3. PD and manganese Manganese may exert a neurotoxic effect, especially at high concentrations, which could be attributed to impaired dopaminergic,

Table 3 Associations between specific metals levels in biological samples and PD. Evidences from case-control studies. Authors

Year

Sample

Cases

Controls

Cu

Mn

Se

Zn

Cr

Hg

Ni

Ahmed Alimonti Baillet Bharucha Bocca Bocca Forte Forte Fukushima Fukushima Fukushima Gazzaniga Gellein Hegde Hozumi Jiménez-Jiménez Jiménez-Jiménez Jiménez-Jiménez Kumudini Ling M.C. Boll M.C. Boll Mariani Ngim and Devathasan Pall Qureshi Squitti Takahashi Tórsdóttir Younes-Mhenni Zhao

2010 2007 2010 2008 2006 2006 2004 2004 2010 2011 2013 1992 2008 2004 2011 1998 1992 1998 2014 2011 2008 1999 2013 1989 1987 2006 2007 1994 1999 2013 2013

B CSF B B CSF H B CSF B B B CSF B B CSF B B CSF B B CSF CSF B B CSF B B B B B B

45 42 24 49 91 91 26 26 82 82 58 11 33 27 20 37 39 37 175 41 22 49 92 54 24 17 65 13 40 48 238

42 20 30 28 18 18 13 13 82 82 81 22 99 25 15 37 39 37 150 26 n.a. 26 112 39 34 21 59 14 40 36 302

+ 0 0 – 0 0 – 0 0 0 0 0 0 + + 0 0 0 + 0 + 0 0 / + 0 + 0 0 – –

+ 0 / / 0 0 0 0 0 + + 0 0 + + 0 / 0 0 / / / / / 0 / / / / / /

– / 0 / / / / / 0 / / / 0 – / / / / / / / / / / / + / 0 / 0 +

– 0 0 / 0 0 / 0 0 0 0 / 0 – + 0 0 – / / / / / / / 0 – 0 / 0 –

0 – / / / / / / / / / / 0 / / / / / / / / / / / / / / / / / /

+ 0 / / / / + / / / / / – + / / / / / / / / / + / / / / / / /

+ 0 / / / / / / / / / / 0 / / / / / / / / / / / / / / / / / /

B = blood; CSF = cerebrospinal fluid; U = Urine; H = Hair; N = Nail; + = Positive association; - = Inverse Association; 0 = No Association; / = Not evaluated. Cu = Copper; Mn = Manganese; Se = Selenium; Zn = Zinc; Cr = Chromium; Hg = Mercury; Ni = Nickel. Notes: For the studies on Iron and blood please refer to: Mostile et al. (2017) (see ref.). For the studies on Iron and CSF please refer to Section 3.3.1 of the main text.

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synuclein accumulation (Tsunemi and Krainc, 2014). Thus, zinc may be implicated in PD neurodegenerative processes by affecting lysosomal functions. However, the few available case-control studies evaluating environmental/occupational exposition to zinc demonstrated no significant association with PD (Gorell et al., 1997; Lai et al., 2002; Seidler et al., 1996). Evidences form studies on blood zinc levels in PD and controls are in agreement with a possible inverse association (Ahmed and Santosh, 2010; Hegde et al., 2004; Squitti et al., 2007a; Zhao et al., 2013), even though there are also available studies with negative (not significant) results (Table 3).

glutamatergic and GABAergic transmission, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The globus pallidus represents the principal anatomic target of manganese neuronal accumulation in the basal ganglia, leading to parkinsonism (Tuschl et al., 2013). The appearance of hyperintense basal ganglia on magnetic resonance imaging T1-weighted images is a pathognomonic sign of such accumulation (Tuschl et al., 2013). Excluding the autosomal recessively inherited disorder of manganese metabolism caused by mutations in the SLC30A10 gene (Quadri et al., 2012), acquired causes of “manganism” include the excessive use of total parenteral nutrition, intravenous methcathinone use, impaired hepatic excretion of manganese leading to acquired hepatocerebral degeneration (Ferrara and Jankovic, 2009), as well as environmental manganism (Tuschl et al., 2013). Individuals with manganese-induced parkinsonism may clinically resemble patients with idiopathic PD, even though dopamine synthesis seems preserved in manganism (Tuschl et al., 2013). Several studies have investigated a possible relationship between chronic manganese overexposure as environmental factor and PD. As for iron, PD seems to be directly associated with occupational exposure to manganese, especially for exposure duration longer than 30 years (Lai et al., 2002; Zayed et al., 1990). In the study of Gorell et al., long-term manganese exposure over 20 years has been significantly associated with PD with an OR of 10.61 (95%CI: 1.06 – 105.83; p = 0.044) (Gorell et al., 1997). Evidences from a longitudinal cohort study of N = 886 American welding-exposed workers followed-up to 10 years were consistent with previous results, showing that progression of parkinsonism increased with cumulative manganese exposure (Racette et al., 2017). When looking at case-controls studies directly evaluating manganese blood levels in PD subjects as compared to controls, different studies addressed in a uniform way towards a positive association between high manganese levels and PD (Ahmed and Santosh, 2010; Hegde et al., 2004; Kumudini et al., 2014; Squitti et al., 2007a) even though no significant results were obtained also in other five detected studies (see Table 3). Less consistent seemed the results obtained from CSF analysis, where higher level of manganese were obtained in one study (Hozumi et al., 2011), while other six detected studies revealed no substantial differences between PD subjects and controls (Alimonti et al., 2007; Bocca et al., 2006; Forte et al., 2004; Gazzaniga et al., 1992; Jiménez-Jiménez et al., 1998; Pall et al., 1987) (Table 3).

3.3.6. PD and other metals Data on possible associations between PD and other metals are poorly represented in literature, showing only for mercury results in agreement towards a possible positive association (Ahmed and Santosh, 2010; Forte et al., 2004; Hegde et al., 2004; Ngim and Devathasan, 1989), while there are inconsistent results from chromium and only a single positive association demonstrated for nickel (Ahmed and Santosh, 2010), based on selected available studies – see Table 3. 4. Discussion Sporadic neurodegenerative disorders recognize a multifactorial aetiology due to a complex interaction between genetic and environmental factors and, among the possible environmental factors, metals have been extensively studied. One of the most important neurotoxic effect of metals is represented by the metal induced production of ROS in the brain (Farina et al., 2013). Since the first case reports suggesting a possible role of past metal exposure in the risk of developing neurodegenerative diseases, a large amount of studies have been performed. Nonetheless, with some exceptions, results have been inconsistent so far. The possible relationship between metals and ALS has been supported by some occupational cohort studies as well as by the identification of some spatial cluster, in particular concerning the exposition to lead and selenium. In a recent ecological study, we demonstrated a higher risk of developing ALS among people exposed to volcanogenic metals in the Mount Etna region (Nicoletti et al., 2016). These results are consistent with those from a previous study on the epidemiology of Multiple Sclerosis in the same area (Nicoletti et al., 2013). More consistent results regard the possible role of lead and this possible association has also been supported by a recent meta-analysis including nine case-control studies (Wang et al., 2014). On the other hand, several case-control studies have evaluated metals concentration in different biological specimens, including blood and CSF, of ALS cases and control subjects, but inconsistent data have been reported. A link between metal and pathological processes has been hypothesized also for AD. However, evidence exists only for aluminum, where both epidemiological studies and case-control evidences suggest a relation. There are also some relevant data supporting the role of mercury as disease-associated factor, from both epidemiological sand case-control studies, where six out of 11 studies found significant increase in mercury blood concentration. Copper levels have not been associated with AD in epidemiological studies, and data from casecontrol studies are inconclusive. However, a meta-analysis of all the aforementioned studies suggested that a slight increase in serum copper may represent a risk factor for AD (Squitti et al., 2014b). Association between PD and metals exposition has been suggested by few available epidemiological and case-controls studies. Concerning iron, there are still not sufficient evidences supporting a possible significant association between iron serum levels and PD, also on the bases of different meta-analysis (Jiao et al., 2016; Mariani et al., 2013). Principal reasons should be sought in the elevated methodological heterogeneity of available studies. A particular attention should be paid on bias and confounding effects to limit heterogeneity among studies

3.3.4. PD and selenium Selenium exerts an important antioxidant activity through selenoproteins, such as the glutathione peroxidase detoxificating hydrogen peroxide and lipid peroxides, which are influenced by selenium levels obtained through diet. Imbalanced levels of selenium may increase oxidative stress implicated in neurodegeneration (Ellwanger et al., 2016). Data from available case-control studies reported not-univoque results, with some studies suggesting higher blood levels of selenium in PD as compared to controls (Qureshi et al., 2006; Zhao et al., 2013), others suggesting instead lower levels (Ahmed and Santosh, 2010; Hegde et al., 2004). The majority of studies on this topic however reported no relevant differences between groups (Baillet et al., 2010; Fukushima et al., 2010; Gellein et al., 2008; Takahashi et al., 1994; Younes-Mhenni et al., 2013) (Table 3). 3.3.5. PD and zinc Impairment of autophagy-lysosomal pathways is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including PD. Mutations in lysosomal-related genes, such as glucocerebrosidase and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD (Dehay et al., 2013). Kufor-Rakeb syndrome is characterized by juvenile-onset parkinsonism, pyramidal signs and dementia caused by mutations in ATP13A2 (PARK9). It has been shown that loss of PARK9 leads to dyshomeostasis of intracellular zinc levels which contributes to lysosomal dysfunction and subsequent alpha89

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Competing interests

and facilitate results summing-up. Data about a possible positive and significant association between manganese and PD seems instead more consistent based on results of long-term exposition as well as on detected differences on serum levels as compared to controls. However, evidences form previous metaanalysis revealed that manganese exposure could be not associated with an increased risk of PD, concluding however that this may not preclude the possibility that high manganese exposure can lead to a manganismrelated parkinsonism (Mortimer et al., 2012). As for the other neurodegenerative disorders, no clear relationship can be drawn from literature for other metals since results are not univocal. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies and the possible pathogenetic role has also been supported by different occupational and ecological studies. However, as previously stated, case-control studies evaluating the metals concentration in the different biological specimens (blood, CSF, nail etc) have generally provided conflicting results reporting both positive, negative or lack of association. Several methodological factors could explain the different results across these studies. The most important consideration regards the timing of the events. Retrospective casecontrol studies generally involve prevalent cases and metal concentration in biological samples reflecting the current exposure rather than the past one. Thus, since the pathogenesis of neurodegenerative diseases considered in this review is thought to begin several years before the onset of symptoms, their use could be inadequate and a possible reverse causality cannot be ruled out. Furthermore, it should be underlined that due to the long interval of time from the biological to the clinical onset in neurodegenerative disorders (e.g. PD), also the use of incident cases does not help in determining the exact sequence of the events. An additional important pitfall concerns the small size of the majority of studies that often have included only a limited number of cases and controls possibly leading to a type-II error. Furthermore, the lack of information on potential confounders, such as dietary factors, plays also a role in the interpretation of these findings. Another element that should be considered is the possible interactions between metals, since they could impact the toxicokinetis. As an example, iron and manganese can compete for the same binding protein in serum (transferrin) and the same transport systems (divalent metal transporter 1) (Klaassen, 2013). At the same time, several polymorphisms could also influence the susceptibility to metals toxicity and hence genetic analysis should ideally be performed. (Klaassen, 2013). Finally the heterogeneity of the biological samples including blood, CSF, nail, hair or urine as well as the different techniques used to evaluate the metals concentration should also be also taken into account in interpreting the results. On the bases of these considerations, it is important to underline that several physiological factors can interact with the concentration of the different metals in the different biological specimens and these factors should be taken into account in performing such type of studies. Thus even if it is highly possible that metals can play a role in the risk of neurodegenerative diseases, up to now few evidences have been provided by retrospective case-control studies.

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