Manganese Accumulation In Brain Research Articles

Restriction of Manganese Intake Prevents the Onset of Brain Manganese Overload in Zip14-/- Mice.

As a newly identified manganese transport protein, ZIP14 is highly expressed in the small intestine and liver, which are the two principal organs involved in regulating systemic manganese homeostasis. Loss of ZIP14 function leads to manganese overload in both humans and mice. Excess manganese in the body primarily affects the central nervous system, resulting in irreversible neurological disorders. Therefore, to prevent the onset of brain manganese accumulation becomes critical. In this study, we used Zip14−/− mice as a model for ZIP14 deficiency and discovered that these mice were born without manganese loading in the brain, but started to hyper-accumulate manganese within 3 weeks after birth. We demonstrated that decreasing manganese intake in Zip14−/− mice was effective in preventing manganese overload that typically occurs in these animals. Our results provide important insight into future studies that are targeted to reduce the onset of manganese accumulation associated with ZIP14 dysfunction in humans.

MRI Automated T1 Signal Intensity Detection of Diffuse Brain Manganese Accumulation in Cirrhosis.

Cirrhosis is associated with diffuse brain manganese deposition, which results in increased signal intensity (SI) in the brain on T1-weighted images, most often visualized in the globus pallidus. The purpose of this study was to determine if automated image intensity measurements can detect SI differences in the basal ganglia and other regions reported to have manganese deposition in patients with cirrhosis compared with controls. T1 FSPGR images were acquired on 28 patients with cirrhosis and 28 age-sex-matched controls. FreeSurfer T1 SI values were obtained for the globus pallidus, putamen, cerebral white matter, cerebral cortex, and brainstem. SI ratios were computed for globus pallidus normalized to white matter and brainstem. SI values and SI ratios were compared between groups using t-tests. Among people with cirrhosis, T1 SI was significantly increased in the globus pallidus, putamen, cerebral white matter, cerebral cortex, and brainstem (P< .001), and the globus pallidus to brainstem ratio was significantly increased (P< .001). No significant difference was seen for globus pallidus to cerebral white matter T1 SI ratio (P = .38). Automatic assessment of T1 SI allows for rapid, objective identification of widespread T1 shortening associated with manganese deposition in cirrhosis, consistent with the global deposition of neurotoxic manganese seen in pathology studies. This automated T1 assessment may have broader utility for other conditions beyond cirrhosis impacting T1 SI.

Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies

Congenital disorders of manganese metabolism are rare occurrences in children, and medical management of these disorders is complex and challenging. Homozygous exonic mutations in the manganese transporter SLC39A14 have recently been associated with a pediatric-onset neurodegenerative disorder characterized by brain manganese accumulation and clinical signs of manganese neurotoxicity, including parkinsonism-dystonia. We performed whole exome sequencing on DNA samples from two unrelated female children from the United Arab Emirates with progressive movement disorder and brain mineralization, identified a novel homozygous intronic mutation in SLC39A14 in both children, and demonstrated that the mutation leads to aberrant splicing. Both children had consistently elevated serum manganese levels and were diagnosed with SLC39A14-associated manganism. Over a four-year period, we utilized a multidisciplinary management approach for Patient 1 combining decreased manganese dietary intake and chelation with symptomatic management of dystonia. Our treatment strategy appeared to slow disease progression, but did not lead to a cure or reversal of already established deficits. Clinicians should consider testing for noncoding mutations in the diagnosis of congenital disorders of manganese metabolism and utilizing multidisciplinary approaches in the management of these disorders.

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of Slc39a14 knockout (Slc39a14-/-) mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that Slc39a14-/- mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, Slc39a14-/- mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using 54Mn reveal that Slc39a14-/- mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of Slc39a14-/- mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in Slc39a14-/- mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in Slc39a14-/- mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in Slc39a14-/- mice suggests that the motor impairments represent lasting effects of early-life Mn exposure.

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition

Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation. This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure. Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures. Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 μg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 μg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R. A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.

Extremely low-frequency magnetic field induces manganese accumulation in brain, kidney and liver of rats

The aim of the present study was to determine the effects of extremely low-frequency magnetic field (ELF-MF) on accumulation of manganese (Mn) in the kidney, liver and brain of rats. A total of 40 rats were randomly divided into eight groups. Four control groups received 0, 3.75, 15 and 60 mg Mn per kg body weight orally every 2 days for 45 days, respectively. The remaining four groups received same concentrations of Mn and were also exposed to ELF-MF (1.5 mT; 50 Hz) for 4 h for 5 days a week during 45 days. Following the last exposure, kidney, liver and brain were taken from all rats and they were analyzed for Mn accumulation levels using an inductively coupled plasma-optical emission spectrometer. In result of the current study, we observed that Mn levels in brain, kidney and liver were higher in Mn groups than in control groups. Mn levels in brain, kidney and liver were also higher in Mn plus ELF-MF groups than in Mn groups. In conclusion, result of the current study showed that the ELF-MF induced manganese accumulation in kidney, liver and brain of rats.

Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: A new treatable disorder

BackgroundThe first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the SLC30A10 gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia.MethodsWe present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in SLC30A10.ResultsThe patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging.ConclusionsWe wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. © 2012 Movement Disorder Society

Changes in Dietary Iron Exacerbate Regional Brain Manganese Accumulation as Determined by Magnetic Resonance Imaging

Manganese (Mn) is an essential metal required for normal homeostasis. Humans chronically exposed to high Mn levels, however, may exhibit psychomotor signs secondary to increased brain Mn. As Mn and iron (Fe) share several cellular membrane transporters, decreased Fe levels resulting from Fe deficiency or anemia lead to increased brain Mn deposition. Conversely, decreased Mn levels are associated with abnormal brain Fe accumulation. To reduce potential Mn toxicity resulting from brain Mn accumulation, we proposed that increased dietary Fe would attenuate brain Mn deposition. To test this hypothesis, three groups of Sprague-Dawley rats were injected weekly (14 weeks) with Mn (3 mg/kg) and fed normal Fe (TX), Fe-supplemented (FeS), or Fe-deficient (FeD) chow. Control (CN) rats received normal dietary Fe and saline injections. Using magnetic resonance imaging, rats were imaged biweekly for 14 weeks to qualitatively monitor brain Mn and Fe accumulation. Both FeS and FeD had greater brain Mn deposition than TX rats. By week 3, R(1) values, which correlate with Mn deposition, were statistically significantly increased (p < 0.05) in brain stem, cerebellum, cortex, midbrain, and striatum compared with CN or TX animals. By week 14, R(1) values for all brain regions in FeS and FeD animals were statistically significantly increased (p < 0.05). By the end of the study, similar results were obtained for R(2) values, a marker of Fe accumulation. These data suggest that Fe supplementation does not effectively protect and may even exacerbate brain Mn accumulation in mammals subchronically exposed to Mn.

Brain Manganese Accumulation is Inversely Related to γ-Amino Butyric Acid Uptake in Male and Female Rats

Iron (Fe) is an essential trace metal involved in numerous cellular processes. Iron deficiency (ID) is reported as the most prevalent nutritional problem worldwide. Increasing evidence suggests that ID is associated with altered neurotransmitter metabolism and a risk factor for manganese (Mn) neurotoxicity. Though recent studies have established differences in which the female brain responds to ID-related neurochemical alterations versus the male brain, little is known about the interactions of dietary ID, Mn exposure, and sex on gamma-amino butyric acid (GABA). Male and female Sprague-Dawley rats were randomly divided into four dietary treatment groups: control (CN), control/Mn supplemented, ID, and ID/Mn supplemented. After 6 weeks of treatment, both ID diets caused a highly significant decrease in Fe concentrations across all brain regions compared to CN in both sexes. Both ID and Mn supplementation led to significant accumulation of Mn across all brain regions in both sexes. There was no main effect of sex on Fe or Mn accumulation. Striatal synaptosomes were utilized to examine the effect of dietary intervention on (3)H-GABA uptake. At 4 weeks, there was a significant correlation between Fe concentration and (3)H-GABA uptake in male rats (p < 0.05). At 6 weeks, there was a significant inverse correlation between Mn concentration and (3)H-GABA uptake in male and female rats and a postitive correlation between Fe concentration and (3)H-GABA uptake in female rats (p < 0.05). In conclusion, ID-associated Mn accumulation is similar in both sexes, with Mn levels affecting GABA uptake in both sexes in a comparable fashion.

Neurologic Spectrum of Chronic Liver Failure and Basal Ganglia T1 Hyperintensity on Magnetic Resonance Imaging

An atypical form of parkinsonism has been described in patients with chronic liver disease, associated with increased T1 signal in the basal ganglia on magnetic resonance imaging. The magnetic resonance imaging signal changes are characteristic of manganese accumulation, which has been neuropathologically confirmed. Manganese neurotoxicity may result in additional neurologic findings besides parkinsonism. To fully characterize patients with chronic central nervous system symptoms and chronic liver failure associated with basal ganglia T1 hyperintensity. Prospective and retrospective case study. Mayo Clinic, Rochester, Minn. Eight patients referred for neurologic evaluation and studied prospectively, and 7 additional retrospectively identified patients who had been examined by Mayo Clinic neurologists. Neurologic syndromes identified. Three syndromes were recognized in these 15 patients with liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: (1) isolated parkinsonism, (2) gait ataxia plus other neurologic findings (ataxia-plus), and (3) cognitive impairment with psychiatric features. All but 1 patient had elevated blood manganese levels. Ammonia levels were normal in most, and the neurologic syndromes did not appear to reflect the well-known toxic-metabolic encephalopathy of liver disease. Chronic liver failure may result in heterogeneous neurologic syndromes that cut across a variety of liver diseases. We selected cases on the basis of evidence of brain manganese accumulation, and this may be a crucial component of these syndromes. Further studies are necessary to explore this issue.

June 28 Highlights

Occupational exposure to manganese can cause parkinsonism. Recent reports suggest that manganese toxicity can occur as a result of exposure to welding fumes; welding has been proposed as a risk factor for Parkinson disease (PD). Joseph Jankovic examines the evidence for and against a relationship between welding, manganese, parkinsonism, and PD. see page 2021 Josephs et al. report eight welders working with inadequate ventilation, presenting with varied neurologic syndromes and pallidal MRI T1 hyperintensity, a biomarker of brain manganese accumulation. The syndromes included atypical parkinsonism, multifocal myoclonus plus mild cognitive impairment, vestibular-auditory dysfunction with truncal ataxia, and isolated mild cognitive impairment. ![][1] Figure. High T1 signal change in the globus pallidus in manganese toxicity from occupational exposure (welding). see page 2033 The editorial by Karl Kieburtz and Roger Kurlan notes that since genetic causes appear identifiable in a minority of PD cases, there has been an extensive search for environmental causes. Two earlier articles in Neurology by Racette et al. described a potential relationship between welding and PD. Manganese, one of the metals found in welding fume, is a neurotoxicant and can lead to a neurologic syndrome with parkinsonian features, which has led to speculation that manganese … [1]: /embed/graphic-1.gif

Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration

For nearly a century, manganese has been recognized as an essential nutrient for proper bone formation, lipid, amino acid and carbohydrate metabolism. While manganese deficiency is characterized by symptoms ranging from stunted growth and poor bone remodeling to ataxia, it is manganese toxicity that is far more devastating from a public health standpoint. Most cases of manganese toxicity are the result of occupational exposure to high levels of the metal, and are characterized by specific neurological symptoms referred to as manganism. While manganism shares many common features with Parkinson's disease, there are distinct differences between the two disorders suggesting that manganism might indirectly affect nigrostriatal dopaminergic function. Recent studies from our laboratory show that dietary iron deficiency is a risk factor for brain manganese accumulation and that the striatum is particularly vulnerable. This review briefly discusses manganese from nutritional and toxicological aspects.

Whole-blood manganese levels and brain manganese accumulation in children receiving long-term home parenteral nutrition.

Recent reports attribute neurological and cerebral disorders to the accumulation of manganese (Mn) in the brain in patients receiving home parenteral nutrition (HPN). It is desirable to control the amount of Mn delivered to these patients, but a suitable method for monitoring an individual's Mn status and assessing Mn accumulation remains debatable. The aim of this study was to evaluate whether whole-blood manganese levels (WB-Mn) correlate with the accumulation of Mn in the brains of children who receive long-term HPN, using magnetic resonance imaging (MRI) of the brain. Six patients who had received HPN (duration of HPN, 18-137 months) were included in this study. The daily parenteral doses of Mn were calculated while on HPN. WB-Mn was measured and T1-weighted MRI of the brain was obtained for each patient with a 1.5-T MR imager. Twelve months after the withdrawal of Mn from HPN, measurements of WB-Mn and brain MRI were repeated in all patients except for one who was lost after initial examination. The same examinations were performed on an additional patient who had been successfully weaned off a 179 month course of HPN 20 months prior to the initial examination. The parenteral dose of Mn while receiving HPN ranged from 15.7 to 91.5 micro g/kg/day. Initially, MRI showed hyperintensity in the globus pallidus in all patients and in the anterior pituitary in one patient. WB-Mn was elevated in four patients, but was in the normal range in the remaining three. Following subsequent measurements 12 months later, WB-Mn was normal in all patients and MRI hyperintensity remained in the globus pallidus in one patient. One patient was lost after the initial examinations. WB-Mn does not necessarily correlate with the accumulation of Mn in the brain. Periodic MRI should be performed in patients receiving long-term NPN to monitor for excessive Mn accumulation in the brain.

Brain manganese accumulation following systemic administration of different forms.

The content and retention of manganese in the blood and brain of mice exposed to different forms of the metal was compared. Mice received an acute sc injection of manganese as the chloride or oxide (Mn3O4) or as the organic MMT. A single injection markedly elevated brain manganese concentrations within 1 day and elevated levels were maintained for at least 21 days. Repeated injections led to further increases in both brain and blood, although the levels in the brain appeared to persist at consistently high levels for longer periods. The chloride form produced higher brain levels than either of the other two forms. These results appear to suggest that the slowly developing neurotoxicity in response to manganese exposure may be due to a persistent retention of manganese by the brain.