Exposure to Manganese

Exposure to manganese can result to CNS damage that can be assessed by postmortem (neuropathologic) examination, neuro-imaging methods, use of biological markers, and neurological examination. Pathological studies indicate that brain damage from manganese involves multiple brain regions. In experimental animals chronically treated with manganese the brain lesions were diffuse, not only involving the basal ganglia but also the cerebral cortex as well as the cerebellum [109].

6.1.1 Relationship with Parkinson's Disease

Autopsy studies of patients who had suffered from manganism showed consistent atrophy of the basal ganglia with loss of neurons and gliosis. The lesions tend to focus in the pallidoluysian system, although the striatum and thalamus may be equally affected [110,111]. A review of previous autopsy cases by Yamada et al. [112] reported the main neuropathological change as a degeneration of the basal ganglia with pallidal lesions found in all examined cases. However, the caudate nucleus and putamen were often affected, whilst the SN, which is predominantly (exclusively) affected in PD, was only slightly damaged. Similar changes were reported in experimental manganese intoxication with the pallidum and subthalamic nucleus found with major lesions [113]. These observations claimed that there are some differences in the neuropathology between chronic manganese intoxication (CMI) and PD, a fact recently emphasised by Olanow [114].

Distribution of Mn in the brain in autopsy cases of CMI using flameless atomic absorption spectrometry showed no significant differences in average concentration between CMI, a PD case, and controls although there were some changes in the distribution, suggesting that the continuation of neurological disorders in CMI is not linked to elevated Mn concentrations in the brain [112]. Involvement of the SN and red nucleus has been reported in some cases of CMI, while Lewy bodies, a hallmark of PD, were identified in SN in one case. However, it is unclear whether or not the patient had PD [115].

More recent neuroimaging studies of symptomatic patients in CMI showed prominent involvement of the globus pallidus, sparing the dopaminergic system [116], while a recent study of a woman with severe liver failure and symmetric hyperintensity of the globus pallidus in MRI images showed increased serum manganese levels, and neuropathological examination of the globus pallidus was consistent with manganese neurotoxicity [117]. Recent positron emission tomography (PET) studies in chronic Mn intoxication, using 99mTc-TRODAT-1, a tracer of dopamine transporter binding, showed a mild decrease of its uptake in the putamen and the ratio of putamen and caudate when compared with normal controls. Although the 99mTc-TRODAT-1 shows a slight decrease in the putamen of manganese patients, the data indicate that the presynapic dopaminergic terminals are not the main target of CMI [118].

In workers from a ferromanganese factory in Taiwan who showed a progressive parkinsonian syndrome after exposure to elevated Mn concentrations, PET studies indicated early effects on presynaptic structures in the nigrostriatal system, including striatum and pallidum [119,120]. Follow-up of five patients with CMI and prominent rigidity, gait disturbances, foot tapping, and writing disorders, revealed that manganese levels had returned to normal and MRI did not show increased T-1 intensities, suggesting that clinical progression continues even 10 years after cessation of Mn exposure [121]. Subsequent PET studies showed preservation of pre- and postsynaptic nigrostriatal dopaminergic functions in patients exposed to manganese [122].

A population-based study on occupational exposure to several heavy metals and the risk of PD conducted in the Henry Ford Health Service revealed a lack of statistical significance for those with low prevalence of exposure, while these findings suggested that chronic occupational exposure to manganese or copper is associated with PD [123].

The pathophysiology of Mn has been reviewed by several authors, e.g., Normandin and Hazell [124], emphasizing that manganese induces damage to mitochondria and is a stimulation cofactor of DNA and RNA polymerases, inducing errors of DNA synthesis.

Manganese exposure can play an important role in causing parkinsonian disturbances, possibly enhancing physiological aging of the brain in conjunction with genetic predisposition. An increased environmental burden of manganese may have deleterious effects on more sensitive subgroups of the population, with subthreshold neurodegeneration in the basal ganglia, generating a pre-parkinsonian condition.

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