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CSF transition metals and Parkinson 497J Neural Transm (1998) 105: 497–505
Cerebrospinal fluid levels of transition metals in patients
with Parkinson’s disease
F. J. Jiménez-Jiménez1, J. A. Molina2, M. V. Aguilar3, I. Meseguer3, C. J.
Mateos-Vega3, M. J. González-Muñoz3, F. de Bustos4,
A. Martínez-Salio2, M. Ortí-Pareja1, M. Zurdo1, and M. C. Martínez-Para3
1Department of Neurology, Hospital Universitario “Príncipe de Asturias”, Alcalá de
Henares, Departments of 2Neurology and 4Biochemistry, Hospital Universitario Doce
de Octubre, and 3Department of Nutrition and Bromatology, Faculty of Pharmacy,
University of Alcalá de Henares, Madrid, Spain
Accepted December 17, 1997; received November 19, 1997
Summary. We compared CSF and serum levels of iron, copper, manganese,
and zinc, measured by atomic absorption spectrophotometry, in 37 patients
with Parkinson’s disease (PD) and 37 matched controls. The CSF levels of
zinc were significantly decreased in PD patients as compared with controls
(p , 0.05). The serum levels of zinc, and the CSF and serum levels of iron,
copper, and manganese, did not differ significantly between PD-patient and
control groups.
There was no influence of antiparkinsonian therapy on CSF levels of none of
these transition metals. These values were not correlated with age, age at
onset, duration of the disease, scores of the Unified Parkinson Disease Rating
Scale of the Hoehn and Yahr staging in the PD group, with the exception of
CSF copper levels with the duration of the disease (r 5 0.38, p , 0.05). These
results suggest that low CSF zinc concentrations might be related with the risk
for PD, although they could be related with oxidative stress processes.
Keywords: Parkinson’s disease, transition metals, iron, copper, manganese,
zinc, cerebrospinal fluid levels, serum levels.
Introduction
The pathogenesis of the neuronal degeneration of neurons in the pars
compacta of the substantia nigra in patients with Parkinson’s disease (PD)
remains unknown. Several studies have shown data suggesting the presence of
oxidative stress in the substantia nigra of PD patients (reviewed by Fahn and
Cohen, 1992; Jiménez-Jiménez and Luquin 1996), although the significance of
these findings is unclear. Increase of iron and other trace metals in the sub-
stantia nigra could hypothetically elicit these processes.
498 F. J. Jiménez-Jiménez et al.
Iron (Halliwell and Gutteridge, 1988), copper (Halliwell and Gutteridge,
1985), and manganese (Donaldson et al., 1992) act as prooxidant agents.
Paradoxically, copper is also essential for the antioxidant function of the
protein ceruloplasmin (Dormandy, 1978), and copper and manganese are
constituents of the cytosolic Cu/Zn- and the mitochondrial Mn-superoxide
dismutases, respectively, which could protect against oxidative processes
(Marttila et al., 1988; Saggu et al., 1989). Zinc has antioxidant activity (Dexter
et al., 1991), is a constituent of the cytosolic Cu/Zn-superoxide dismutase
(Marttila et al., 1988; Saggu et al., 1989), and has a stabilizing influence on
membranes (Chvapil, 1976).
Many studies have shown increased iron concentrations in the substantia
nigra of PD patients (for review see Gerlach et al., 1994; Jiménez-Jiménez and
Luquin, 1996). In addition, it has been reported increased zinc (Dexter et al.,
1989, 1991), decreased copper (Dexter et al., 1989, 1991; Riederer et al., 1989;
Uitti et al., 1989) and normal manganese concentrations in the substantia
nigra of PD patients (Dexter et al., 1991, 1992; Larsen et al., 1981).
There is little information concerning CSF concentrations of transition
metals in patients with PD. The aim of this study was to assess the lumbar
cerebrospinal fluid levels of iron, copper, manganese and zinc in patients with
PD compared with a control population.
Patients and methods
We assessed the cerebrospinal fluid and serum levels of iron, copper, zinc, and manganese
in 37 patients with PD recruited from outpatients attended in the Neurology Departments
of 2 urban Hospitals. They fulfilled diagnostic criteria for PD (Hughes et al., 1992)
and were evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn
et al., 1987) and the Hoehn and Yahr staging (1967). Eight patients were untreated,
while the other 29 were treated with antiparkinsonian drugs alone or in combination
including levodopa (26 cases), bromocriptine or pergolide (25 cases), and deprenyl (8
cases).
The control group comprised 37 “healthy” patients, who underwent lumbar puncture
because of suspected (but not confirmed) subarachnoid hemorrhage or pseudotumor
cerebri, oculomotor palsies or other indications in the usual neurological survey. Routine
CSF analysis was normal in each patient or control. Informed consent was obtained in
each case. The clinical features of both groups are summarized in Table 1.
The following exclusion criteria were applied to both patients and controls: A)
Ethanol intake higher than 80g/day in the last 6 months. B) Previous history of chronic
hepatopathy or diseases causing malabsorption. C) Previous history of severe sys-
temic disease. D) Atypical dietary habits (diets constituted exclusively by one type of
foodstuff, such as vegetables, fruits, meat, or others, special diets because of religious
reasons, etc). E) Previous blood transfusions, anemia, and policytemia, F) Intake of
supplements of iron, copper, aluminum, zinc, or chelating agents, G) Therapy with
chlorotiazides, ACTH, or steroids, H) Acute infectious disorders, traumatisms or surgery
in the last 6 months.
Lumbar CSF and venous blood samples were taken from each fasted patient or
control between 8.00 and 10.00 a.m. The blood samples were collected on ice and centri-
fuged. Traumatic spinal punctures were excluded from the study. The CSF and serum
specimens were frozen at 230°C and protected from light exposure with aluminum foil
until analysis. The determinations were performed blindly.
An atomic absorption spectrophotometer (AAS, model 3110) equiped with an elec-
trothermal atomizer (model HGA 400) and an autosampler (all from Perkin-Elmer,
CSF transition metals and Parkinson 499
Table 1. Clinical data and results of PD patient and control groups. Data of quantitative
variables are expressed as mean 6 SD. PD Parkinson’s disease, ADL activities of
daily living
PD-patients Controls
n 5 37 n 5 37
Clinical data
Age (years) 65.7 6 8.8 62.4 6 17.8
Female 23 21
Male 14 16
Age at onset of PD (years) 58.7 6 9.8
Duration of PD (years) 7.0 6 6.4
Scores of the Unified PD
Rating Scale (UPDRS)
Total (items 1–31) 39.3 6 15.9
ADL subscale (items 5–17) 16.8 6 8.4
Motor subscale (items 18–31) 21.6 6 7.4
Hoehn and Yahr stage 2.9 6 1.1
Transition metals levels
Iron
CSF (mg/l) 0.17 6 0.17 0.21 6 0.15
Serum (mg/l) 1.01 6 0.33 0.95 6 0.30
Copper
CSF (µg/l) 104.9 6 86.3 109.1 6 88.2
Serum (mg/l) 1.06 6 0.31 0.94 6 0.27
Zinc
CSF (mg/l) 0.10 6 0.06*A 0.17 6 0.14*A
Serum (mg/l) 0.82 6 0.23 0.77 6 0.17
Manganese
CSF (µg/l) 1.20 6 0.98 0.88 6 0.76
Serum (µg/l) 0.93 6 0.81 1.22 6 0.59
Nutritional markers (serum)
Retinol (µmol/l) 1.89 6 0.53 1.84 6 0.51
Total proteins (g/dl) 7.1 6 0.5 7.2 6 0.5
Albumin (g/dl) 4.4 6 0.4 4.3 6 0.5
*A: p , 0.05
Beaconsfield, Bucks, UK) were used for the analysis of iron, copper, and manganese in
the CSF. The instrument parameters are shown in Table 2. The furnace operating condi-
tions were slightly modified (Table 3) to eliminate matrix interference and to maximize
data reproductibility and the life span of the graphite tubes. CSF specimens were centri-
fuged at 3,500rpm for 5 minutes, and 500µl of the supernatant were appropriately diluted
with 0.5% nitric acid. Quadruplicate aspirations were averaged for calculations. CSF zinc
concentrations were measured using a Perkin-Elmer 2380 spectrophotometer according
to Meret and Henkin (1971).
Copper and zinc were determined in serum by AAS using a Perkin-Elmer
2380 spectrophotometer after the proper dilution (1/4). The iron analysis was carried
out by AAS using a Perkin-Elmer 2380 spectrophotometer according to Olson and
Hamlin (1969). The instrument parameters are shown in Table 4. Serum manganese
levels were performed with the same working conditions than those used for the CSF
analysis.
500 F. J. Jiménez-Jiménez et al.
Table 2. Instrumental conditions of the electrothermal atomic absorption
spectrophotometer 3110, equiped with HGA 400
Manganese Iron Copper
Wavelenght (nm) 279.5 248.3 324.8
Slit width (nm) 0.2 0.2 0.7
Mode Peak area Peak area Peak area
Inert gas Argon Argon Argon
Lamp current (mA) 30 30 30
Integration time (s) 6 6 6
Sample volume (µl) 20 20 20
Background correction Deuterium lamp None None
Table 3. Furnace operating conditions of the electrothermal atomic absorption
spectrophotometer 3110
Step Temperature (°C) Ramp time Hold time Argon
(sec) (sec) flow-rate
Mn Fe Cu Mn Fe Cu Mn Fe Cu (ml/min)
1. Dry 110 100 110 10 20 15 30 10 20 3
2. Charring 1,400 1,400 900 10 20 15 10 20 20 3
3. Atomization 2,200 2,400 2,000 1 1 0 5 4 4 0
4. Cleaning 2,650 2,650 2,650 1 1 1 2 2 3 3
Table 4. Instrumental conditions of the flame atomic absorption spectrophotometer 2380
Iron Copper Zinc
Wavelenght (nm) 248.3 324.8 213.9
Slit width (nm) 0.2 0.7 0.7
Lamp current (mA) 30 30 30
The lamps were of hollow-cathode type. The standard curves were prepared by using
standard solutions (Titrisol, E. Merck, Darmstadt, Germany) under the same conditions
than those used for the samples. All the analyses were performed by quadruplicate. The
recoveries for iron, copper, zinc, and manganese were, respectively, 97.5 6 2.3, 95.3 6 1.7,
98.0 6 4.1 and 96.3 6 5.4%. The interday coefficients of variations, both for CSF and
serum, were 12.05, 3.09, 3.51, and 3.53%; and the within-day coefficients of variation 0.17,
0.03, 0.36 and 0.29%, respectively.
The results were expressed as mean 6 SD. The statistical analysis used the
Biostatistical Packet of “R-Sigma Data Base” (Horus Hardware) (Moreu et al., 1990),
and included the two-tailed student’s t test, ANOVA, and calculation of Pearson’s
correlation coefficient when appropriate.
CSF transition metals and Parkinson 501
Results
The results are summarized in Table 1. The mean CSF and serum levels of
iron, copper, zinc, and manganese did not differ significantly from those
of controls, with the exception of CSF zinc levels, that were significantly
decreased in PD patients as compared with controls. There was also no
significant differences in the serum levels of a number of nutritional markers
(retinol, total proteins, albumin), between the two study groups. Anti-
parkinsonian therapy did not influence significantly the CSF levels of the
metals that were measured (Table 5).
There was no significant correlation in PD patients between the CSF or
serum levels of iron, copper, zinc, and manganese and the following values:
age, age at onset of PD, duration of PD, scores of the UPDRS (total and
subtotals of Activities of Daily Living and motor examination), and the
Hoehn and Yahr staging, with the exception of CSF copper concentrations
and duration of the disease (r 5 0.38, p , 0.05).
Discussion
In the last decade there has been an increasing interest for the possible role of
transition metals in the pathogenesis of PD. Since the first report by Dexter et
al. (1987), many investigators found increased iron concentrations in the
substantia nigra (for revision see Gerlach et al., 1994; Jiménez-Jiménez and
Luquin, 1996). In the present study we found normal CSF iron concentrations,
as it was previously reported (Gazzaniga et al., 1992; Pall et al., 1987; Pan et
al., 1997; Takahashi et al., 1994). In addition, CSF ferritin (Dexter et al., 1990;
Kuiper et al., 1994; Pall et al., 1990) and transferrin concentrations are normal
(Loeffler et al., 1994). However, the results on serum iron levels are contro-
versial. In the present and other previous study by our group (Cabrera-
Valdivia et al., 1992), using stringent exclusion criteria, we found normal
serum iron concentrations, a finding that is in agreement with other authors
Table 5. Influence of antiparkinsonian treatment on CSF levels of transition metals
(mean 6 SD)
Iron Copper Zinc Manganese
(mg/l) (µg/l) (mg/l) (µg/l)
Levodopa
Yes (n 5 26) 0.19 6 0.17 113.6 6 90.4 0.10 6 0.05 1.02 6 0.75
No (n 5 11) 0.12 6 0.17 83.5 6 75.8 0.11 6 0.10 1.62 6 1.33
Dopamine agonist
Yes (n 5 25) 0.17 6 0.15 115.8 6 91.9 0.10 6 0.04 1.06 6 0.89
No (n 5 12) 0.18 6 0.21 78.3 6 68.0 0.12 6 0.09 1.49 6 1.12
Deprenyl
Yes (n 5 8) 0.17 6 0.23 117.8 6 109.8 0.11 6 0.05 1.51 6 1.21
No (n 5 29) 0.17 6 0.16 102.4 6 83.5 0.10 6 0.07 1.11 6 0.91
502 F. J. Jiménez-Jiménez et al.
(Chen et al., 1992; Pan et al., 1997, Takahashi et al., 1994). Moreover, 24 hour
urinary excretion of iron has reported to be normal by our group (Cabrera-
Valdiviva et al., 1994). In contrast with these data, Abbot et al. (1992), and
Logroscino et al. (1997), the latter in a recent population study, reported
decreased serum iron levels.
Pall et al. (1987), and more recently Pan et al. (1997) reported raised
copper concentration in the CSF of patients with PD. Pall et al. (1987) sug-
gested that this metal might be raised in brain. However, two groups reported
decreased levels of copper in the substantia nigra of parkinsonian patients
(Dexter et al., 1989, 1991; Uitti et al., 1989). Serum levels of copper
(Campanella et al., 1973; Jiménez-Jiménez et al., 1992; Pall et al., 1987) and
ceruloplasmin (Campanella et al., 1973; Jiménez-Jiménez et al., 1992) were
normal in previous studies with the exception of decreased copper levels in a
single study (Pan et al., 1997). In agreement with our results other groups
reported normal CSF copper (Gazzaniga et al., 1992; Takahashi et al., 1994)
and ceruloplasmin concentrations (Loeffler et al., 1994).
Dexter et al. (1989, 1991) reported increased zinc levels in the substantia
nigra, lateral putamen, and caudate nucleus in patients with PD. The authors
related this increase of zinc to an attempt of protection against oxida-
tive stress. Other authors have not found alterations in zinc levels in
parkinsonians’ brain (Riederer et al., 1989; Uitti et al., 1989). Serum zinc
levels have been reported to be normal (Jiménez-Jiménez et al., 1992) or
decreased (Abbot et al., 1992; Pan et al., 1997). In this study, we found
decreased CSF zinc levels, in contrast with the normal ones found in other
previous shorter studies (Pan et al., 1997; Takahashi et al., 1994), but serum
zinc levels were normal.
Finally, brain (Dexter et al., 1991; Dexter et al., 1992; Larsen et al., 1981),
CSF (Gazzaniga et al., 1992; Pall et al., 1987; Pan et al., 1997), and serum
manganese levels were normal (Jiménez-Jiménez et al., 1995; Pan et al., 1997)
in previous studies, as it was the case in this report.
A recent epidemiological study have shown that occupational study to
copper, manganese, and to the combinations lead-copper, lead-iron, and iron-
copper, were associated with the risk for PD (Gorell et al., 1997). In contrast,
dietary habits of PD patients regarding consumption of foodstuffs rich in iron,
copper, zinc, and manganese, were similar to those of their spouses (Ayuso-
Peralta et al., 1997).
The results of the present study showed as the main result a decrease of
CSF levels of zinc, and there was no correlation between the CSF iron, zinc,
copper, and manganese levels and the analyzed clinical features of PD. These
results suggest that low CSF zinc concentrations might be related with the risk
for PD, although they also could be related with oxidative stress processes and
with the pathogenesis of this disease.
Acknowledgments
This work was supported in part by the grants FIS 97/1262, 97/5227, 97/5228, and 97/5578
and by the “Fundación Neurociencias y Envejecimiento”.
CSF transition metals and Parkinson 503
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Authors’ address: F. J. Jiménez-Jiménez, C/Corregidor José de Pasamonte, 24, 3-D,
E-28030 Madrid, Spain.
