Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.

[Cognitive dysfunctions caused by excessive exposure to manganese compounds. Cognitive disturbances in intravenous users of ephedrone (methcathinone) with manganese compounds]. / Zaburzenia funkcji poznawczych spowodowane nadmierna ekspozycja na zwiazki manganu. Zaburzenia funkcji poznawczych u dozylnych uzytkowników preparatów efedronu (metkatynonu).

Intravenous injection of self-produced ephedrone (metcathinone) using potassium permanganate as an oxidant can lead to severe, fixed encephalopathy. This risk applies mainly to young individuals experimenting with "home-made" drugs and results in an irreversible aggravation of overall functioning. Besides multiple neurological symptoms and movement disorders, affected individuals also experience cognitive dysfunction. No systematic research has been conducted in this field. Single case reports and small group descriptions show that assessment with screening tools such as the Mini-Mental State Examination (MMSE) is ineffective. Neuropsychological assessment conducted with other tests indicates significant dysarthric speech disorders, psychomotor function impairment, attentional disorders of varying intensity as well as dysfunctions of verbal and visual working memory processes. Some studies of this group of subjects also indicate working memory and executive function disorders. These dysfunctions seem to be permanent and do not recede following manganese use discontinuation and an improvement of the neuroradiological picture in MRI assessment. A standard test battery should be developed enabling the assessment of both cognitive and neurological dysfunctions that otherwise render some tests impossible to administer.

Evaluation of cognitive characteristics of patients developing manifestations of parkinsonism secondary to long-term ephedrone use.

AIM: In this study, cognitive functions of 9 patients developing parkinsonism due to chronic manganese intoxication by intravenous methcathinone solution were investigated using detailed neuropsychometric tests. METHOD: Attention deficit, verbal and nonverbal memory, visuospatial function, constructive ability, language, and executive (frontal) functions of 9 patients who were admitted to our clinic with manifestations of chronic manganese intoxication and 9 control subjects were assessed using neuropsychometric tests. Two years later, detailed repeat neuropsychometric tests were performed in the patient group. The results were evaluated using the χ(2) test, Fisher's exact probability test, Student's t test and the Mann-Whitney U test. RESULTS: While there was no statistically significant difference between the two groups in language functions, visuospatial functions and constructive ability, a statistically significant difference was noted between both groups regarding attention (p = 0.032), calculation (p = 0.004), recall and recognition domains of verbal memory, nonverbal memory (p = 0.021) and some domains of frontal functions (Stroop-5 and spontaneous recovery) (p = 0.022 and 0.012). Repeat neuropsychometric test results of the patients were not statistically significant 2 years later. CONCLUSION: It has been observed that cognitive dysfunction seen in parkinsonism secondary to chronic manganese intoxication may be long-lasting and may not recover as observed in motor dysfunction.

[Encephalopathy caused by intravenous potassium permanganate used for illegal production of methcathinone (ephedrone) from medicines containing pseudoephedrine]. / Encefalopatia spowodowane dozylnym uzywaniem preparatów zawierajacych nadmanganian potasu stosowany jako reagent w produkcji metkatynonu (efedronu) z leków zawierajacych pseudoefedryne.

Encephalopathy caused by manganese compounds used for illicit production of ephedrone (methcathinone) is described. The onset of disease could be observed after some months of regular intravenous use of ephedrone contaminated with manganese. In clinical picture dominate neurological signs and symptoms, mainly extrapyramidal syndromes: parkinsonism, tremor, muscle distonia, pro- and retropulsion. Some other symptoms may be observed: hypophonia or dysarthria, gain disturbances, impairment of precise movement, and micrographia. In cranial NMR often appears bilaterally an increase of an intensity of T1 signal in globus pallidus and in some other brain structures. Elimination of manganese with the use of chelating therapy as well as symptomatic treatment, mainly with the antyparkinsonic drugs, seems to be ineffective.

A case of acute prochloraz-manganese complex intoxication treated with extracorporeal elimination.

BACKGROUND/AIM: We treated a patient with critical manganese intoxication with vigorous extracorporeal elimination. In this article, we describe the clinical characteristics and treatment modalities of the patient. PATIENT: A 65-year-old man was brought to the emergency room (ER) 5.5 h after ingesting prochloraz-manganese complex. He experienced circulatory collapse and went into a coma without self-breathing on arrival at the ER. Mechanical ventilation was initiated and hemoperfusion, hemodialysis and continuous venovenous hemodiafiltration were performed with the help of norepinephrine. MEASUREMENT AND RESULT: The manganese levels on the first, second and fourth hospital days were 34.1, 23.6 and 12.5 µg/l, respectively. He recuperated from the shock state within 7 hospital days. After 4 critical weeks, the patient regained full consciousness. CONCLUSION: Rigorous extracorporeal elimination by hemoperfusion, hemodialysis and continuous venovenous hemodiafiltration was an effective treatment modality for patients with acute manganese intoxication.

Neuromotor function in ship welders after cessation of manganese exposure.

PURPOSE: The aim of the present study was to investigate whether previous long-term exposure to manganese (Mn) via inhalation of welding fumes can cause persistent impairment in neuromotor function even long after cessation of exposure. METHODS: Quantitative tests of tremor, motor speed, manual dexterity, diadochokinesis, eye-hand coordination and postural stability were administered to 17 retired ship welders (mean age 69 years), with mean exposure time 28 years. The welders' exposure had ceased on average 18 years before the study. A cumulative exposure index (CEI) was calculated for each of the former welders. The welders were compared with 21 referents from the same shipyards (mean age was 66 years). RESULTS: Former welders performed less well than referents in the grooved pegboard test, and poorer performance was associated with CEI. The performance in most of the other neurobehavioral tests was similar between groups, but the welders tended to perform slightly better than the referents in tests demanding hand steadiness. The latter finding may be due to a training effect from their former working tasks or selection bias into or out of this occupation. CONCLUSIONS: In the present study of welders with previous welding fume exposure, former welders and referents performed similarly in most of the neurobehavioral tests. Previous adverse effects on the neuromotor system might have ceased, and decreased neuromotor function due to normal aging processes in both groups might have disguised any slight effect of previous Mn exposure. The poorer performance in the grooved pegboard test among welders may indicate an adverse effect on motor function of long-term exposure to Mn, but this finding has to be confirmed by other studies.

[Manganism--neurodegenerative brain disease caused by poisoning with manganese]. / Manganizm--choroba neurodegeneracyjna mózgu spowodowana zatruciem manganem.

Manganism is a neurodegenerative disease of brain caused by intoxication by manganese and its excessive accumulation in this tissue. Some of the clinical symptoms observed in this disease resemble these observed in Parkinson disease.

The association of bone and blood manganese with motor function in Chinese workers.

Manganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (ß=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand ß=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand ß=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (ß = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand ß=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam ß=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, ß = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.

A Parkinsonian syndrome in methcathinone users and the role of manganese.

BACKGROUND: A distinctive extrapyramidal syndrome has been observed in intravenous methcathinone (ephedrone) users in Eastern Europe and Russia. METHODS: We studied 23 adults in Latvia who had extrapyramidal symptoms and who had injected methcathinone for a mean (+/-SD) of 6.7+/-5.1 years. The methcathinone was manufactured under home conditions by potassium permanganate oxidation of ephedrine or pseudoephedrine. All patients were positive for hepatitis C virus, and 20 were also positive for the human immunodeficiency virus (HIV). RESULTS: The patients reported that the onset of their first neurologic symptoms (gait disturbance in 20 and hypophonia in 3) occurred after a mean of 5.8+/-4.5 years of methcathinone use. At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward; 11 patients were falling daily, and 1 of these patients used a wheelchair. Twenty-one patients had hypophonic speech in addition to gait disturbance, and one of these patients was mute. No patient reported decline in cognitive function. T(1)-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users. Among the 13 former users (2 to 6 years had passed since the last use), lesser degrees of change in the MRI signal were noted. Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users. The neurologic deficits did not resolve after patients discontinued methcathinone use. CONCLUSIONS: Our observation of a distinctive extrapyramidal syndrome, changes in the MRI signal in the basal ganglia, and elevated blood manganese levels in methcathinone users suggests that manganese in the methcathinone solution causes a persistent neurologic disorder.

Manganese body burden in children is associated with reduced visual motor and attention skills.

Manganese (Mn) is an essential element, however, children with moderate to high Mn exposure can exhibit neurobehavioral impairments. One way Mn appears to affect brain function is through altering dopaminergic systems involved with motor and cognitive control including frontal - striatal brain systems. Based on the risk for motor and attention problems, we evaluated neurobehavioral function in 255 children at risk for Mn exposure due to living in proximity to coal ash storage sites. Proton Induced X-ray Emissions (PIXE) analysis was conducted on finger and toenails samples. Multiple neuropsychological tests were completed with the children. Fifty-five children had Mn concentrations above the limit of detection (LOD) (median concentration = 3.95 ppm). Children with detectable Mn concentrations had reduced visual motor skills (ß = -5.62, CI: -9.11, -2.12, p = 0.008) and more problems with sustained attention, based on incorrect responses on a computerized attention test, (ß = 0.40, CI: 0.21, 0.59, p < 0.001) compared with children who had Mn concentrations below the LOD. Findings suggest that Mn exposure impacts attention and motor control possibly due to neurotoxicity involving basal ganglia and forebrain regions. Visual-motor and attention tests may provide a sensitive measure of Mn neurotoxicity, useful for evaluating the effects of exposure in children and leading to better treatment options.

Association of exposure to manganese and fine motor skills in welders - Results from the WELDOX II study.

The aim of this study was to evaluate the effect of exposure to manganese (Mn) on fine motor functions. A total of 48 welders and 30 unexposed workers as controls completed questionnaires, underwent blood examinations, and a motor test battery. The shift exposure of welders to respirable Mn was measured with personal samplers. For all subjects accumulations of Mn in the brain were assessed with T1-weighted magnetic resonance imaging. Welders showed normal motor functions on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale part III. Furthermore welders performed excellent on a steadiness test, showing better results than controls. However, welders were slightly slower than controls in motor tests. There was no association between fine motor test results and the relaxation rates R1 in globus pallidus and substantia nigra as MRI-based biomarkers to quantify Mn deposition in the brain.

[Brain MRI associated with chronic hepatic failure and hypermanganism]. / Hypersignal T1 bipallidal dans le cadre d'une cirrhose avec hypermanganésémie.

INTRODUCTION: Hypermanganism is primarily linked to inhalation exposure. Several observations of exogenous manganese poisoning have been reported associating neuropsychiatric symptoms, parkinsonian syndrome and hyperintensities of the two pallida on T1 weighted sequences on brain MRI. Recently, similar neurological and radiological signs have been described without exogenous exposure to manganese but in the framework of endogenous poisoning particularly in chronic hepatic failure. CASE REPORT: We report the case of a 41-year-old HIV-positive and HVC-positive man who presented psychomotor impairment associated with bipallidal T1 hyperintensities on the brain MRI. The diagnosis of a hypermanganesemia was made on blood samples. We present a literature review on exogenous and endogenous hypermanganesemia and discuss differential diagnosis in the radiological setting of bipallidal T1 hyperintensities. CONCLUSION: Bipallidal T1 hyperintensities on brain MRI may suggest hypermanganism even in the clinical setting of a non-specific neurological disorder such as psychomotor impairment.

Characteristic of neuropsychological deficits in patients diagnosed with manganese encephalopathy due to ephedrone use - case series analysis. / Charakterystyka deficytów neuropsychologicznych u pacjentów z rozpoznana encefalopatia manganowa zazywajacych efedron ­ analiza przypadków.

AIM: The study presents neuropsychological characteristic of 16 individuals with manganese-induced parkinsonism due to intravenous ephedrone use. MATERIAL AND METHODS: Overall cognitive function screening as well as full examination of various cognitive domains (verbal learning, visual memory, working memory, executive functions, construction and visuospatial functions) with the use of elastic neuropsychological test battery were performed. Dyshartric speech disorders were also precisely evaluated. Additionally, all individuals filled in the Beck Depression Inventory (BDI), which is used to assess mood. RESULTS: All patients had evident dysarthric speech disorders accompanied with palilalia and writing disorders (micrographia) in the majority of investigated individuals. Neuropsychological screening diagnosis showed no overall cognitive deficits at the level of dementia. Mild decrease in verbal learning and visual memory processes was found; as well as ideomotor but no construction praxis disorders. Results of working memory and executive function assessment indicated decrease in cognitive flexibility and logical conceptualization abilities, as well as set-shifting disorders. Patients varied significantly in their severity of executive dysfunction. Duration of ephedrone use was found nonsignificant for patients' cognition. The mean BDI score indicated moderate depression. Higher level of depressive symptoms was associated with poorer overall cognitive screening, decrease of visual and verbal learning as well as phonemic verbal fluency.

Spectrum of movement disorders in professional welders.

OBJECTIVE: To examine the clinical presentation of movement disorder in patients who reported a history of welding. METHODS: A retrospective chart review during a three-year period was performed on all movement disorders and patients who had been welders were identified. The clinical presentation of these patients was categorized by the movement disorder at the time of the initial neurological evaluation and by the therapy response. A comparison group was created by randomly selecting four non-welders for each welder. RESULTS: Among 1126 charts reviewed, eleven patients presented with a welder history. Parkinsonism was a common presentation in both groups: three of the eleven welders (27%) and five of the forty-one controls (12%). Dystonia was also common with 27% and 20%, respectively. Using the chi-squared analysis, the prevalence rates for both parkinsonism and dystonia were similar to controls. All of the welder patients with parkinsonism responded to dopaminomimetic therapy. Six of the eleven welders had elevated manganese levels in either blood or urine. CONCLUSIONS: Welders who present with a movement disorder such as parkinsonism or dystonia, have the prevalence rates for these disorders similar to the non-welder population (Fig. 2, Ref. 15).

Welding-related brain and functional changes in welders with chronic and low-level exposure.

Although an essential nutrient, manganese (Mn) can be toxic at high doses. There is, however, uncertainty regarding the effects of chronic low-level Mn-exposure. This review provides an overview of Mn-related brain and functional changes based on studies of a cohort of asymptomatic welders who had lower Mn-exposure than in most previous work. In welders with low-level Mn-exposure, we found: 1) Mn may accumulate in the brain in a non-linear fashion: MRI R1 (1/T1) signals significantly increased only after a critical level of exposure was reached (e.g., ≥300 welding hours in the past 90days prior to MRI). Moreover, R1 may be a more sensitive marker to capture short-term dynamic changes in Mn accumulation than the pallidal index [T1-weighted intensity ratio of the globus pallidus vs. frontal white matter], a traditional marker for Mn accumulation; 2) Chronic Mn-exposure may lead to microstructural changes as indicated by lower diffusion tensor fractional anisotropy values in the basal ganglia (BG), especially when welding years exceeded more than 30 years; 3) Mn-related subtle motor dysfunctions can be captured sensitively by synergy metrics (indices for movement stability), whereas traditional fine motor tasks failed to detect any significant differences; and 4) Iron (Fe) also may play a role in welding-related neurotoxicity, especially at low-level Mn-exposure, evidenced by higher R2* values (an estimate for brain Fe accumulation) in the BG. Moreover, higher R2* values were associated with lower phonemic fluency performance. These findings may guide future studies and the development of occupation- and public health-related polices involving Mn-exposure.

Dissociation of reward and effort sensitivity in methcathinone-induced Parkinsonism.

Methcathinone-induced Parkinsonism is a recently described extrapyramidal syndrome characterized by globus pallidus and substantia nigra lesions, which provides a unique model of basal ganglia dysfunction. We assessed motivated behaviour in this condition using a novel cost-benefit decision-making task, in which participants decided whether it was worth investing effort for reward. Patients showed a dissociation between reward and effort sensitivity, such that pallidonigral complex dysfunction caused them to become less sensitive to rewards, while normal sensitivity to effort costs was maintained.

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity.

Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson's disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration.

The neuropathology of manganese-induced Parkinsonism.

Manganese is an essential trace metal that is widely used in industry, particularly in the manufacture of steel. Exposure to high levels of manganese can cause neurotoxicity with the development of a form of parkinsonism known as manganism. It has recently been hypothesized that manganese exposure might also cause or accelerate the development of Parkinson disease (PD). This article is a review of the pathologic studies that have been reported in patients with manganism and in primates experimentally intoxicated with manganese. They demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies. This finding contrasts with what is seen in PD, in which there is preferential degeneration of dopamine neurons in the substantia nigra pars compacta coupled with Lewy bodies and preservation of the pallidum. These pathologic findings do not support the notion that manganese causes PD but rather argues that manganese-induced parkinsonism and PD are distinct and separate disease entities.

Manganese-induced Parkinsonism associated with methcathinone (Ephedrone) abuse.

BACKGROUND: Manganese intoxication may lead to a levodopa-resistant, akinetic-rigid syndrome. A new form of presumed manganese poisoning has been reported in drug-addicted persons from Russia, Ukraine, and Estonia who have intravenously injected self-prepared methcathinone hydrochloride (Ephedrone). PATIENT: A 36-year-old man from Azerbaijan with hepatitis C and only modest hepatic synthetic dysfunction developed rapid-onset, levodopa-resistant parkinsonism with profound hypophonia. CONCLUSION: Ephedronic encephalopathy outside the region of the former Soviet Union may become a more widespread public health problem as a result of global travel and the easy availability of the recipe for synthesis of methcathinone on the Internet.

Manganic encephalopathy due to "ephedrone" abuse.

We describe the clinical and neuroimaging features of 6 drug-abuse patients with self-inflicted manganese poisoning. The patients injected a home-brewed mixture called "ephedrone" (slang term) that contained manganese to produce an amphetamine-like euphoria. The desired chemical product, phenylpropanoneamine (also called methcathinone), was synthesized from a common-cold-remedy compound using permanganate as the catalyst. Manganese was a by-product in the ephedrone mixture. After months of self-injections, a clinical picture emerged, consisting of apathy, bradykinesia, gait disorder with postural instability, and spastic-hypokinetic dysarthria. There was no response to levodopa. The MRI revealed symmetric hyperintense T1-weighted signals in the basal ganglia, typical of manganese accumulation.