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© 1991 S. Karger AG, Basel
0014-3022/91/0311-0007S2.75/0
Eur Neurol 1991;31:7-11
Manganese, Selenium and Other Trace Elements in Spinal Cord,
Liver and Bone in Motor Neurone Disease
J.D. Mitchella, B. W. Eastb, I.A. Harrisb, B. Pentlandc
“Department of Neurology, Royal Preston Hospital, Sharoe Green Lane, Preston; bScottish Universities Research and Reactor
Centre, East Kilbride, Glasgow, and c Rehabilitation Medicine Unit, Astley Ainslie Hospital, Grange Loan, Edinburgh, UK
Key Words. Motor neurone disease • Amyotrophic lateral sclerosis • Trace elements • Selenium • Manganese
Abstract. Trace element levels were measured by neutron activation analysis in spinal cord, liver and bone of 7
control patients dying of non-neurological disease and 15 patients dying of motor neurone disease (MND). The
concentration of selenium was significantly elevated in the cervical cord, liver and bone in the MND group. Although
spinal cord manganese levels were increased at both the cervical and thoracic levels, the hepatic concentration was
reduced in the MND patients. These findings are discussed in relation to current understanding of the pathogenesis
of MND.
Trace elements were first linked with neurological
disease over 150 years ago when 4 patients who devel­
oped a parkinsonian syndrome [1] following extensive
occupational exposure to manganese were reported.
Manganese-induced parkinsonism has since been widely
studied [2], Copper [3] and iron [4] have also been stud­
ied in Parkinson’s disease.
Although toxic heavy metals such as lead and mer­
cury have been widely discussed in motor system degen­
eration, studies of essential and non-essential trace ele­
ments have been sparse. Motor neurone disease (MND)
is a relentlessly progressive disorder, the cause of which
is not yet known. Studies of trace elements in MND
have so far yielded conflicting results [10]. Altered spi­
nal cord and erythrocyte manganese levels have been
reported by two groups [6-8]. Increased spinal cord,
liver [6] and erythrocyte [8] selenium levels have been
found as have reduced cerebrospinal fluid (CSF) cobalt
levels [9]. This area has recently been critically reviewed
[ 10].
Much of this previous work has been based on small
numbers of patients and controls. Groups have not
always been well matched. Results from tissue samples
from 5 MND patients and 5 controls were previously
published by us [6]. This series has now increased to 15
MND patients and 7 control subjects. The final results of
this programme are presented here.
Methods
Specimens of spinal cord, liver and bone were collected from
patients dying of MND (table 1) and non-neurological diseases (ta­
ble 2). Necropsy was undertaken within 24 h of death. Blocks of
spinal cord were taken at three levels: cervical, mid-thoracic and
lumbar enlargement levels as well as liver and bone. The experimen­
tal methods were exactly as those previously described [6]. Magne­
sium, manganese, chromium, iron, cobalt, zinc, rubidium, caesium,
selenium, antimony, silver and copper were measured. Batch to
batch variation was assessed by processing NBS bovine liver (US
National Bureau of Standards, Washington, DC), a certified materi­
al, in parallel with the experimental specimens. The analysis was
done blind as to the origin of each sample.
Statistical analysis was based on non-parametric methods using
Spearman’s correlation coefficient, the Mann-Whitney U test and
the Friedman two-way analysis of variance by ranks.
Results
Spinal cord manganese levels were significantly in­
creased in the MND patients at both the cervical (p =
0.044, Mann-Whitney U test) and thoracic (p = 0.016,
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Introduction
Mitchell/East/Harris/Pentland
8
Table 1. The control group - general and clinical features
No.
Age at death
years
Sex
Cause of death
Other conditions
39
87
F
pyelonephritis
staghorn calculus
40
66
M
bronchopneumonia
adenocarcinoma of colon
41
59
F
acute myocardial infarction
pulmonary hamartoma
42
73
M
acute on chronic cardiac failure
hypertension
43
68
F
acute myocardial infarction
pulmonary thromboembolism
44
74
F
squamous cell carcinoma of oesophagus
aspiration pneumonia;
no métastasés outside regional lymph nodes
45
75
M
cholangiocarcinoma of liver
pulmonary thromboembolism
Age at death
years
Sex
Clinical course
1
68
F
bulbar palsy and neurogenic atrophy of intrinsic hand muscles when first seen; progressive course
for 2 years until death
2
53
M
presented with weakness of left hand; this became generalised with profuse fasciculation and
inexorable progression to death after 2 Vi years
3
26
F
presented with weakness of right arm and leg 15 months before death; quickly developed signs of
generalised disease with bulbar palsy in final weeks
4
71
M
developed weakness of left arm 3 years before death; progressed to generalised disease with marked
muscle wasting; bulbar palsy in last 3 months of life
5
60
F
presented with pseudobulbar palsy 18 months before death; inexorable course with neurogenic
atrophy of limb muscles in later stages
6
76
M
developed leg weakness 18 months before death; progressive course with bulbar palsy in final stages
7
70
F
presented with generalised weakness and bulbar palsy 2 years before death
8
69
F
presented with weakness affecting legs more than arms 2 years before death; bulbar palsy in final
stages
9
64
M
presented 3 years before death with left hemiparesis and wasting of small hand muscles; developed
spastic paraparesis with bulbar palsy in last 3 months of life
10
80
F
presented with bulbar palsy followed by progressive wasting and weakness of all limbs, dying 2
years after onset
11
68
F
presented with left foot drop and spastic paraparesis, with progression to all limbs; bulbar palsy in
last 6 months, dying 2 'h years after onset
12
55
F
presented with bilateral foot drop and bulbar palsy; died 3 months later
13
84
F
presented with weight loss and progressive muscle wasting 3 yean prior to death; bulbar palsy in
last 3 months
14
59
F
presented 2 yean before death with slurring dysarthria; progressive coune with neurogenic atrophy
in legs in final 6 months
15
71
M
presented with weakness of both legs 8 months prior to death; soon developed bulbar palsy,
punuing a relentlessly progressive coune
No.
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Table 2. The patient group - clinical features
9
Trace Elements in MND
121
2.0
2
6
CD
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p = 0.044
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Controls
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MND
Controls
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-C
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4
1.0
♦
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4
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MND
4
0.5
Controls
*
MND
Controls
Miyata et al
0
Fig. 1. Tissue manganese levels in MND.
2.0
0.5
0.8
p = 0.044
p = 0.0014
!c
o>
| 0.6
t
4
0.4
0.2
*t
♦
Controls
r
0.4
o>
©
5
1.0
*
t
MND
Ol 0.5
O
!
a.
0.2
o>
Controls
MND
2
*
t
0.1 -I
Controls
MND
©*
©
0.0
£o> W
'©
1
T3
4
4
p = 0.0066
*
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e■o
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8
8
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o
+
0.0J
3 o.o
Fig. 2. Tissue selenium levels in MND.
No significant differences between the two groups
were found for magnesium, chromium, iron, cobalt,
zinc, rubidium, caesium or antimony. Silver and copper
were not determined in sufficient subjects to allow statis­
tical analysis. There were no correlations between age
and any of the trace elements measured.
Discussion
These results support previous reports of increased
spinal cord selenium [5, 6] and manganese [6, 7] levels in
MND and confirm elevated hepatic selenium concentra­
tions in MND patients compared with controls dying of
non-neurological disease [6], This is the first report of
increased bone selenium and reduced hepatic manga­
nese levels in MND. Out of a wide range of elements,
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Mann-Whitney U test) levels. By contrast, hepatic man­
ganese levels were significantly reduced (p = 0.02, MannWhitney U test) in the MND patients (fig. 1). The corre­
lation between the thoracic and lumbar manganese levels
in the MND patients (p = 0.023, Spearman rank correla­
tion) was not found in the controls.
Spinal cord selenium levels were significantly in­
creased in the MND patients at the cervical level (p =
0.044, Mann-Whitney U test), but not at the other two
cord sites. Selenium levels were lowest in the thoracic
cord and highest at the lumbar enlargement in both
groups. This topographical variation was significant in
the control population (p = 0.027, Friedmann analysis of
variance by ranks) but not in the MND patients. Hepatic
(p = 0.0014, Mann-Whitney U test) and bone (p =
0.0066, Mann-Whitney U test) selenium levels were also
increased in the MND patients (fig. 2).
only manganese and selenium showed significant differ­
ences between the two groups. All others showed close
concordances.
The existence of a parkinsonian syndrome in manga­
nese toxicity is well established [2], Manganese was first
linked with MND with the report of a foundry worker
who developed MND at an early age [10]. There is now
agreement between independent groups that spinal cord
manganese levels are elevated in MND [6, 7], The mea­
surements reported here correspond closely with those of
Miyata et al. [7] (fig. 1). This group used anterior hom
tissue (AHT) rather than the whole cord segments (WCS)
used in this work. The authors felt that AHT levels
would correspond more closely to motor neuronal levels
but the increased handling needed to separate AHT sub­
stantially increases the risk of contamination. WCS were
used in this work in order to reduce this risk as far as
possible. In contrast with Miyata et al. significant differ­
ences were only found at the cervical and thoracic levels
(fig. 1). A third group has also reported high AHT con­
centrations in two MND patients as compared with a
single control [5].
No specific function is known for manganese in the
spinal cord. The manganoenzyme glutamine synthetase
accounts for 80% of brain manganese content [11]. The
relationship of the high spinal cord levels to increased
CSF glutamate, aspartate and glycine concentrations in
MND [12] is uncertain. Glutamate and aspartate recep­
tor agonists can damage cortical neurones [ 13] and it has
been suggested that calcineurin requires manganese for
activity [14],
The reduced hepatic manganese level might merely
reflect the previously reported low erythrocyte concen­
trations [8] as no attempt was made to remove blood
from the samples before analysis.
The increased selenium in cervical cord, liver and
bone with the previously reported increase in erythro­
cyte levels [8] suggests a general accumulation in MND.
Although this might be thought to represent increased
dietary intake, this is unlikely. If this were the explana­
tion, increased urinary levels would be expected. Others
have found these to be normal in MND [15]. While
MND has been associated with seleniferous areas [16],
its prevalence is not altered in Finland, a well known
selenium-deficient area [17], It seems likely that there is
some other explanation for these observations.
Abnormal nucleic acid metabolism has been reported
in MND [18]. An underlying defect of enzymatic motor
neuronal DNA repair mechanisms has been suggested
[19], This attractive hypothesis is difficult to test and is
Mitchell/East/Harris/Pcntland
so far unsupported [20]. Selenium has anti-carcinogenic
and anti-mutagenic effects at nutritional levels. This is
thought to follow increased DNA repair activity. This
would be difficult to reconcile with defective DNA repair
in the face of high spinal cord levels. At higher concentra­
tions a genotoxic action has been described [21], Sodium
selenite can induce substantial DNA damage without
influencing DNA repair in human fibroblasts [22], Dis­
ruption of DNA by selenium could therefore provide an
alternative explanation for the nucleic acid changes in
MND. Spinal cord selenium was however only signifi­
cantly increased at the cervical level. The most impressive
differences were in liver and bone. It is difficult to envis­
age that the selenium levels reached the concentration of
>0.5 mM necessary to exert a genotoxic effect [22],
The selenoenzyme glutathione peroxidase is impor­
tant in free-radical inactivation and accounts for 20% of
total brain selenium content in rat [14]. Manganese con­
taining superoxide dismutase has a similar role and ele­
mental manganese is able to initiate free-radical-me­
diated processes. The variations in the distribution of
selenium and manganese may reflect abnormal free-radi­
cal activity in MND. Although no clear evidence of this
has so far emerged [23], this possibility is still not
excluded.
The protective effect of selenium against the effects of
heavy metal toxicity [24] should also be considered in
relation to work attempting to link MND with metals
such as mercury and lead. The increased selenium levels
reported here might result from the accumulation of
heavy metals. Selenium also modifies the toxicity of
other substances. Nitrofurantoin and paraquat are rela­
tively less toxic in the replete state whereas the deleteri­
ous effects of paracetamol, iodipamide and aflatoxin Bi
are enhanced [25], The high selenium levels might either
represent a protective response to an environmental fac­
tor implicated in the pathogenesis of MND or alterna­
tively they may potentiate the harmful effects of such a
substance.
No correlation was found between manganese and
selenium levels and nutritional status or between the dis­
tribution of these elements throughout the spinal cord
and the pattern of clinical involvement. Information on
tissue trace element levels in other neurological diseases
is limited and appropriate studies are necessary to deter­
mine whether the findings described here are specific for
MND. Trace elements are essential for a wide range of
metabolic processes and precisely how these results re­
late to the pathogenesis of MND remains not only an
enigma but also an exciting challenge.
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10
Trace Elements in MND
The authors are indebted to their clinical colleagues in Preston
and Edinburgh for allowing access to material from their patients.
We are also grateful to the pathologists of the Western General Hos­
pital, Edinburgh and the District Laboratory, Preston for assistance
in obtaining specimens. The preparation of this material for publi­
cation was supported by the Motor Neurone Disease Research Fund
of the Royal Preston Hospital.
12 de Belleroche J, Recordati A, Clifford Rose F: Elevated levels of
13
14
15
16
References
17
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Received: September 12, 1989
Accepted: December 7, 1989
J.D. Mitchell, FRCP
Department of Neurology
Royal Preston Hospital
Sharoe Green Lane
Preston, PR2 4HT (UK)
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Acknowledgements
11
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