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Review Article

High Signal Intensities on T1-Weighted MRI as aBiomarker of Exposure to Manganese

Yangho KIM

Department of Occupational and Environmental Medicine, Ulsan University Hospital, #2903 Cheonha-Dong,Dong-Ku, Ulsan 682-060, South Korea

Received January 16, 2004 and accepted February 3, 2004

Abstract: Increased signal in T1-weighted images was observed in the experimental manganese

(Mn) poisoning of the non-human primate and a patient with Mn neurointoxication. However, ourstudy showed that the increased signals in magnetic resonance images (MRI) were highly prevalent(41.6%) in Mn-exposed workers. Especially 73.5% of the welders showed increased signal intensities.Blood Mn concentration correlated with pallidal index. These changes in MRI tend to disappearfollowing the withdrawal from the source of Mn accumulation, despite permanent neurologicaldamage. Thus increased signal intensities on a T1-weighted image reflect exposure to Mn, but notnecessarily manganism. Our study also showed that the concentration of Mn required to produceincreased signal intensities on MRI is much lower than the threshold necessary to result in overtclinical signs of manganism. Increased signal intensities in the globus pallidus were determined byMn accumulation in the animal experiment. All these results strongly suggest that signal intensitiesin T1-weighted MRI reflect a target site dose in a biologically-based dose-response model. At which

increase of signal intensity, the progression of manganism from Mn exposure occurs, however, remainsto be solved.

Key words: Increased signal intensities, Magnetic resonance image, Manganism, Manganese exposure,Pallidal indices, Target site dose

Introduction

Several valuable studies 16) have been published on therelation of manganese (Mn) exposure with high signalintensities on T1-weighted brain magnetic resonance images(MRI) in Korea since the detection of high signals in Koreanwelders exposed to Mn in 1997. However, the fact thathigh signal intensities on T1-weighted MRI can be a usefulbiomarker of exposure to Mn was relatively unknown inthe field of occupational medicine. The objectives of thepresent paper are 1) to review the history and the presentissue of the research on the high signals on T1-weightedMRI as a biomarker of exposure to Mn, and thus 2) tocontribute to improving the human health risk assessmentsof Mn exposure.

Mn can cause a parkinsonian syndrome. In occupationalsettings inhalation is the main route of exposure to Mn. AfterMn is absorbed in the lungs, the absorbed Mn is transportedin the blood, primarily in the divalent oxidation state (Mn 2+),and cross the blood-brain barrier (BBB) via specific carriersat a rate far slower than in other tissues. Mn transport acrossthe BBB occurs both in the 2+ and 3+ oxidation state 7). TheMn ion (Mn 2+) has five unpaired electrons in the 3d orbit,which results in its large magnetic moment, causing theshortening of T1-relaxation time and an increase in signalintensity on T1-weighted MRI. Because of the paramagneticquality of Mn, the bilateral symmetrical increase in signalintensities, confined to the globus pallidus and midbrain,can be observed on T1-weighted MRI, but with no alterationon the T2-weighted image (Fig. 1). However, Mn induced

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high signals in T1-weighted MRI do not show any abnormalfindings in brain computed tomography (CT) 5). The increasedsignal in T1-weighted images was observed in theexperimental Mn poisoning of the non-human primate 8, 9) .Nelson, et al . also reported increased signal intensities in apatient with Mn neurointoxication 10). The Mn-induced highsignals in MRI usually disappear within six months or oneyear following the withdrawal from the source of Mnaccumulation 1, 3, 10, 11) . Furthermore, the characteristic highsignals were reported to be also frequently observed in

asymptomatic workers exposed to Mn 2). A similar MRIpattern has been also observed in patients receiving totalparenteral nutrition, because of excessive Mn intake 12, 13) ,and in patients with liver failure, due to their inability toclear Mn through biliary excretion 5, 1416) .

Signal Intensities in T1-weighted MRI as aTarget Site Dose

The increased signal in T1-weighted images was observed

in the experimental Mn poisoning of the non-humanprimate 8, 9) and a patient with Mn neurointoxication 10) .However, our study showed for the first time that thecharacteristic high signals were also frequently observed inasymptomatic workers exposed to Mn 2). We showed thatthe increased signals in MRI were highly prevalent (41.6%)in Mn-exposed workers. Especially 73.5% of the weldersshowed increased signal intensities although none of thenon-exposed clerical workers showed the increased signal.Blood Mn concentration correlated with pallidal index (PI)

which was defined 17) as the ratio of the signal intensity of globus pallidus to subcortical frontal white matter in axialT1-weighted MRI planes multiplied by 100 ( =0.41). BloodMn concentration also increased PI and exposed workersalso had higher PI than non-exposed manual as well as clericalworkers. These changes in MRI tend to disappear followingthe withdrawal from the source of Mn accumulation, despitepermanent neurological damage 1, 8, 10 11) . All these findingssuggest that increased signal intensities on a T1-weightedimage reflect exposure to Mn, but not necessarily manganism.

Fig. 1. T1-weighted MR image in a welder exposed to manganese (top) and a worker without manganese exposure(bottom). Arrows indicate increased signal intensities at the globus pallidus.(a) Axial T1-weighted MR image (b) Sagittal T1-weighted image (c) Axial T2-weighted image.

a b c

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Compatible with some experimental animal studies 8, 1820)

our study showed that the concentration of Mn required toproduce increased signal intensities on MRI is much lowerthan the threshold necessary to result in overt clinical signsof manganism 2).

Newland and Weiss related more subtle behavioral effectsto increased pallidal signals in the absence of overt clinicalsigns in the primate 20) . The finding that increased signalintensities were observed in the globus pallidus most frequently,was compatible with the fact that the globus pallidus was theepicenter for damage induced by Mn 2, 8, 15, 19) . Increased signalintensities in the globus pallidus were determined by Mnaccumulation in the animal experiment 8). All these resultsstrongly suggest that signal intensities in T1-weighted MRIhave the sensitivity to quantify excessive Mn concentrationsin the globus pallidus of Mn-exposed humans, in whom brainMn concentrations, like environmental Mn concentrations,may remain relatively stable. Hence, signal intensities inT1-weighted MRI reflect a target site dose in a biologically-based dose-response model 21).

Mn-Induced High Signals Should be Differentiatedfrom High Singnals due to Others

Similar patterns of increased T1-weighted signal intensitiescan be associated with lipid 22) , hemoglobin breakdownproducts 23 ) , melanoma 24) , neurofibromatosis 25) , andcalcification 26, 27) . However, iron deposits cause a moremarked shortening of T2-relaxation time compared to T1-relaxation time, which results in a low signal intensity inthe T2-weighted image, allowing clear distinction of ironand Mn deposits. Melanoma and neurofibromatosis can alsobe differentiated from Mn deposits from knowledge of thesite and symmetry of the signals. The signal intensity of calcification can be shown as diminished, null effect, orincreased in T1-weighted MRI 2632) . Increased signal is onlyseen with low concentration of calcium, and the signalintensity progressively decreases as the calciumconcentrations increase above 3040% by weight 27) .

However, in all situations, the extent and degree of calcification are much clearer at brain CT 31, 33) . Calcification-induced signals therefore can be ruled out by normal CTfindings 6).

Implication of High Signals on T1-WeightedMRI in the Field of Occupational Health

Target site dose of MnMany studies suggest blood Mn is an inadequate biomarker

of Mn exposure on an individual basis because blood Mndoes not correlate with the current levels of Mn airconcentration or duration of Mn exposure in an individualworker. However, elevated measures of blood Mn levelsmay be useful in monitoring exposures for a group of workers,because group means of blood Mn significantly correlatedwith past integrated exposure 3438) . Blood Mn has a half lifeof 1042 d, whereas brain has a much longer half life up tomore than 200 d 3941) . Increased signal intensities in basalganglia as a target site dose reflect Mn accumulated in brainfor more than several months. Thus, increased signalintensities as a target site dose can be a more usefulbiomarkers of Mn than other biological indicies such asambient Mn concentration or blood Mn concentration onan individual basis. Furthermore, the further human researchusing the target site dose of Mn could clarify the continuumof Mn-associated symptomatology, and improve humanhealth risk assessments.

Diagnosis of manganismThe diagnosis of manganism in industrial workers can

usually be made when an extrapyramidal symptom complexsuch as parkinsonism develops in workers exposed to Mn.Clinical features of manganism are, however, similar to thoseof idiopathic Parkinson disease (IPD). It may be difficultto distinguish manganism and IPD from each other. Thereare several clinical distinctions between the two clinicalentities 3, 42) . Lack of tremor as a predominant feature, earlydystonia, postural impairment early in the course of theillness, peculiar walking, the so-called cock walk, difficultyin backward walking, and the failure to have a response tolevodopa therapy may help to differentiate manganism fromIPD.

Increased signal intensities on a T1-weighted image donot necessarily indicate manganism although they are verysensitive indicies of Mn exposure. Moreover, the Mn-inducedhigh signals usually disappear within one year followingthe withdrawal from the source of Mn accumulation, despitepermanent neurologic damage 1, 8, 10, 11) . Hence, the findings

of 18F-6-fluorodopa positron emission tomography (PET)or dopamine transporter single-photon emission computedtomography (SPECT) should be provided in discriminatingbetween IPD and manganism in addition to increased signalintensities on a T1-weighted MRI 1, 3, 4) .

Research Needs

First, the procedure to determine the PI should bestandardized for minimizing variance due to differences of

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MRI machines, their parameters, or the readers.Second, at which increase of signal intensity, the

progression of manganism from Mn exposure occurs,however, remains to be solved. An animal model of manganism with increased signal intensities would help, butdifferent routes of exposure and different species is a limitingfactor, hence a prospective study correlating the increasesin T1 signal intensities in Mn-exposed workers with clinicaland neuropsychological findings is necessary.

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