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Echogenicity of the Substantia Nigra
Association With Increased Iron Content and Marker for Susceptibility to Nigrostriatal Injury
Daniela Berg, MD;
Wolfgang Roggendorf, MD;
Ute Schröder;
Rüdiger Klein, MD;
Thomas Tatschner, MD;
Peter Benz, MD;
Oliver Tucha, PhD;
Michael Preier, MSc;
Klaus W. Lange, MD;
Karlheinz Reiners, MD;
Manfred Gerlach, PhD;
Georg Becker, MD
Arch Neurol. 2002;59:999-1005.
ABSTRACT
Background Patients with Parkinson disease characteristically exhibit an increased
echogenicity of the substantia nigra (SN) on transcranial sonography, a new
neuroimaging technique. The same echo feature of the SN can be identified
in 9% of healthy adults.
Objective To evaluate the relevance of the echogenic SN in healthy adults.
Design In the first part of the study, 10 healthy subjects younger than 40
years with a distinct SN hyperechogenicity underwent extensive neurological,
motor, neuropsychological, and fluorine 18-dopa positron emission tomographic
([18F]-dopa PET) examinations. Results were compared with those
of 10 subjects with a low echogenic SN. In the second part of the study, the
postmortem brains of 20 patients without extrapyramidal disorders during their
lifetime were sonographically examined with a particular focus on SN echogenicity.
Subsequently, one half of the brain was prepared for heavy metal analysis,
the other for a histological examination.
Results Healthy subjects with SN hyperechogenicity exhibited a significant reduction
of the [18F]-dopa uptake, especially in the putamen (Wilcoxon matched
pair test: left side, P = .006; right side, P = .009), whereas their neuropsychological and motor performance
were normal. Postmortem studies showed that the echogenicity of the SN correlated
with its iron content.
Conclusions Increased echogenicity of the SN, characteristically seen in Parkinson
disease, is related to a functional impairment of the nigrostriatal system
(even in young healthy adults) that can be revealed by [18F]-dopa
PET studies. Substantia nigra hyperechogenicity is related to a higher tissue
iron level, which is known to enhance the cells' generation of reactive oxygen
specimens. Therefore, we hypothesize that transcranial sonography may identify
a susceptibility marker for the development of nigral injury that can be detected
early in life, prior to the onset of Parkinson disease.
INTRODUCTION
CURRENT treatment of Parkinson disease (PD) is basically symptomatic.
So far, no neuroprotective strategy has proved to be effective in the clinical
setting, although concepts and results of animal experiments have been promising.1 One important reason for the failure of neuroprotection
may be the fact that nigrostriatal degeneration has advanced to a 60% to 70%
reduction of neurons in the substantia nigra (SN) at the time when the first
clinical symptoms of PD are noticed by the patient.2
It is possible that at this stage of the disease, drugs with a potential neuroprotective
effect are no longer capable of arresting or slowing the course of degeneration.
However, the speed of neurodegeneration might be reduced by the commencement
of neuroprotective treatment in an earlier (preclinical) stage of PD.
Recent studies have shown that transcranial sonography (TCS) may identify
an important susceptibility marker for nigral injury.3
This is a new neuroimaging technique that provides a 2-dimensional sonographic
depiction of the brain parenchyma through the intact skull.4
In patients with PD, an increase of echogenicity in the SN can be depicted
using TCS even though results of computed tomographic scans and magnetic resonance
imaging are known to be normal in these patients.5
The echo pattern of the SN found in PD can be identified in approximately
9% of healthy adults.3, 5 To evaluate
the relevance of this characteristic sonographic feature, healthy subjects
with SN hyperechogenicity underwent fluorine 18-dopa positron emission tomography
([18F]-dopa PET). In this pilot study, subjects with SN hyperechogenicity
exhibited a significantly reduced [18F]-dopa uptake of the striatum,
indicating a subclinical impairment of the dopaminergic nigral neurons.3
The cause of the increase in SN echogenicity is unclear. The similarity
in echo pattern of the SN between patients with PD and subjects with a subclinical
impairment of the nigrostriatal system has led to the hypothesis that one
of the pathological or biochemical hallmarks of PD may also be a causative
factor in the increased echogenicity seen in healthy volunteers. An increase
in tissue levels of iron6-8
and gliosis9 are 2 of several processes that
occur within the SN in the course of PD that may also affect the echogenicity
of the tissue.10
Our study was launched to clarify the relation between increased SN
echogenicity and susceptibility to nigral cell injury. In the first part of
the study, we assessed nigral function using [18F]-dopa PET in
young healthy subjects with and without SN hyperechogenicity to test whether
the association between increased SN echogenicity and nigral neural impairment
could be identified in this age group. In the second part, reasons for the
increase in tissue echogenicity of the SN were investigated by studying postmortem
brains and correlating ultrasonographic and neurochemical findings.
SUBJECTS AND METHODS
[18F]-DOPA PET STUDIES OF HEALTHY VOLUNTEERS WITH A HYPERECHOGENIC
SN
We identified 10 healthy subjects younger than 40 years with a distinct
increase in SN echogenicity (mean ± SD age, 26.7 ± 7.6 years;
3 women and 7 men, all right-handed). Identification and selection of subjects
were performed as described previously.3 Subjects
were selected from a group of 120 members and students of the University of
Würzburg (Würzburg, Germany). Subjects with a hyperechogenic SN
with an echogenic signal extension of more than 0.25 cm2 on at
least 1 side (prevalence, 9%) and no central nervous system disorders were
included in this study. Eleven subjects fulfilled these criteria, and 10 of
them gave their informed consent according to the Declaration of Helsinki11 to participate in further examinations, including
a thorough neurological examination, comprehensive motor and neuropsychological
testing, and an [18F]-dopa PET examination. For comparison, we
selected 10 healthy controls (3 women, 7 men; mean ± SD age, 40 ±
15.5 years) with areas of low SN echogenicity (area of hyperechogenic signal
of the SN < 0.2 cm2) matched for sex and IQ who had already
undergone the [18F]-dopa PET protocol in the same nuclear medicine
center at the PET Center of the University of Mainz (Mainz, Germany) in the
last 12 months. The selection of the control group was performed according
to the recommendation of the ethics committee of the University of Würzburg.
Following the proposal, we accepted an older age of control subjects because
the age-related decline in [18F]-dopa uptake would lessen the differences
among a group of subjects with nigral injury and the control group. Control
subjects also had an [18F]-dopa PET study, a sonographic examination,
and a motor and neuropsychological test battery.
Neuroimaging
For the TCS examination, we used a color-coded phased-array ultrasound
system equipped with a 2.5-MHz transducer. The examination was performed through
the preauricular acoustic bone window using standard techniques as described
previously,3-5
with the aim of identifying the SN as clearly as possible within the hypoechogenic
mesencephalic brainstem. Because the signal brightness (echogenicity) is not
quantifiable using ultrasound, the area of hyperechogenic signals in the SN
region was encircled and measured. All individuals were assessed independently
by 2 experienced TCS investigators. The average values of both measurements
of each side were used for further analysis. The TCS examiners were blinded
to the results of the PET study and the neuropsychological assessments.
Positron emission tomographic scans were performed on an ECAT EXACT
47 tomograph (Siemens, Erlangen, Germany), which provided 47 simultaneous
planes with a physical slice thickness of 3.7 mm in a field of view of 16.2
cm. The thickness of the reoriented slice used in the analysis was 6.07 mm.
The axial resolution (full with half-maximum) was less than 6 mm, and the
in-plane resolution was less than 5.5 mm. Standard techniques as described
previously were used for the [18F]-dopa PET scans.3
Activity ratios were calculated as the ratio of the specific [18F]-dopa
uptake in the caudate nucleus and putamen divided by the mean uptake in the
occipital cortex. In addition, influx constants (Ki) were calculated from
the right and left caudate and putamen by using a modified compartment model
approach with an occipital nonspecific tissue rather than a plasma input function.3
Motor and Cognitive Examinations
Motor function was assessed using a pegboard examination and a series
of foot- and finger-tapping tests for a period of 32 seconds.3, 12
In the neuropsychological assessment, standardized psychometric test
procedures were used to measure memory (Digit Span Forward and Digit Span
Backward of the Wechsler Memory Scale–Revised),13
attention (Alertness and Divided Attention task of the Computerized Neuropsychological
Assessment of Attention Deficits),14 and executive
functions (S Word Test, H/T
Word Test, and the Tower of London Test).13-14
The examiner assessing motor and cognitive performance was unaware of the
TCS and PET results.
ANALYSIS OF THE POSTMORTEM SN AND RELATION OF SN ECHOGENICITY TO BIOCHEMICAL
AND HISTOLOGICAL PARAMETERS
In the second part of the study, we compared the echo pattern of the
SN with histological and neurochemical findings to identify the cause of the
increased echogenicity. We examined the postmortem brains of 20 patients (6
women and 14 men; median age, 51 years; range, 38-59 years). None of the patients
had experienced any extrapyramidal disorder (including PD) prior to death,
and no subject had died of a neurological disorder. One patient had a history
of epileptic seizures, and another had a history of meningoencephalitis. The
average period between death and autopsy was 48 hours (range, 6-144 hours).
After autopsy, an ultrasound examination was performed with the unfixed
brains immersed in a vessel filled with isotonic sodium chloride. For this
examination we used the same ultrasound system as for the clinical investigations,
with a 5-MHz transducer held under the surface of the fluid. For ultrasound
system indexes, we chose a penetration depth of 4 to 8 cm and a dynamic range
of 50 dB with high persistence. Image brightness and time gain compensation
were adapted as needed for each investigation. The brain was placed upside
down in the vessel to achieve an optimal picture of the SN. The whole brain
was scanned in coronal and axial planes. Attention was focused on the SN region,
where hyperechogenic areas were encircled and measured. The average area of
hyperechogenic signals of both SNs was related to the neurochemical and histopathological
findings.
After the ultrasound examination, all brains were divided midsagitally.
The left half was stored at -80°C; the other half was fixed for
10 to 14 days in a solution of 4% paraformaldehyde.
Preparation of Tissue Samples for Trace Metal Analysis
Dissection of the hemisphere was performed when the temperature of the
brain had risen to -10oC. The brain was coronally sectioned
into slices approximately 10 mm thick. The SN was identified anatomically
and dissected. Brain tissue was stored in plastic vessels.
Assessment of Total Iron, Copper, Manganese, Zinc, and Calcium Levels
in SN Tissue
Brain specimens of approximately 50 mg were weighed and dried for 2
hours at 105°C. Nitric acid (250 mL, suprapure) was added, and the mixture
was incubated overnight. The mixture was completely digested at 56°C for
2 hours. Diluted samples were measured with a polarized Zeman atomic absorption
spectrophotometer (Z-8100; Hitachi, Tokyo, Japan) according to standard procedures.
Concentrations were calculated from external and internal standards in the
following ranges: 0.5 to 4 mg/mL (iron), 12 to 100 ng/mL (copper), 1.25 to
10 ng/mL (manganese), 0.25 to 2 mg/mL (calcium), and 1.25 to 10 ng/mL (zinc).
Histopathological Analysis
Dissected areas included the neocortex (Brodmann areas 5, 8, 9, 17,
18, 19, 21, 22, and 40), limbic areas (Brodmann area 24 and the hippocampus),
striatum, thalamus, brainstem (SN and pons with the locus coeruleus and medulla),
and cerebellum. All paraffin sections were stained with hematoxylin-eosin.
Sections of the basal ganglia and SN were stained for iron using the Prussian
blue stain. Additionally, selected areas were silver impregnated using the
Bielschowsky method and stained for Luxol fast blue.
Immunohistochemistry was performed in selected cortical areas (Brodmann
areas 9, 21, 22, 24, and 40), the SN, the locus coeruleus, and the hippocampus
according to a standard protocol (peroxidase-antiperoxidase method). These
specimens were incubated with phosphorylation-dependent anti- antibodies
(AT8; dilution, 1:800; Immunogenetics, Gent, Belgium),15
ubiquitin antibodies (dilution, 1:200; DAKO, Glostrup, Denmark), and  -synuclein
antibodies (dilution, 1:2000; Chemicon, Temecula, Calif).16
The quality of immunohistochemistry was checked by using control specimens
from patients with Lewy body dementia (for -synuclein antibodies),
Alzheimer disease (AT8 and ubiquitin antibodies), and PD.
Biochemical and histological parameters were obtained by investigators
blinded to the other results and to those of the ultrasound examination.
STATISTICAL ANALYSIS
Descriptive statistics are given as the median with lower and upper
quartiles (25th and 75th percentiles). Intergroup comparison was performed
using the U test, Wilcoxon matched pair test, and
Kruskal-Wallis test; correlation analysis was done using the Spearman rank
correlation and multiple regression analysis. Differences were assumed to
be significant at P<.05.
RESULTS
[18F]-DOPA PET STUDIES OF HEALTHY VOLUNTEERS WITH AN INCREASED
AREA OF SN HYPERECHOGENICITY
In the 10 healthy subjects with SN hyperechogenicity, the median extension
of hyperechogenic signals was 0.31 cm2 (range, 0.28-0.35 cm2) for the right SN and 0.31 cm2(range, 0.28-0.34 cm2) for the left SN (Figure 1).
The control group had a median echogenic SN area of 0.11 cm2 (range,
0.08-0.12 cm2) on the right side and 0.14 cm2(range,
0.09-0.15 cm2) on the left side. Differences were highly significant
(Wilcoxon test: Z = 2.8; P = .005). Differences in
SN areas between the left and right sides were not significant in the group
of controls (Wilcoxon test: Z = 1.4; P = .16) or
in the group of subjects with SN hyperechogenicity (Wilcoxon test: Z = 1.93; P = .06).
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Figure 1. A, Mesencephalic brainstem with
normal findings on transcranial sonography (axial scanning plane). Number
1 indicates the butterfly-shaped mesencephalic brainstem surrounded by the
hyperechogenic basal cisterns; arrow, the echogenic border zone of the brainstem
raphe; and asterisk, the aqueduct. B, Subject with hyperechogenic substantia
nigra on the ipsilateral (arrowheads) and contralateral (encircled) side,
depicted within the peduncles of the mesencephalic brainstem (1). Arrow indicates
the brainstem raphe; asterisk, the aqueduct.
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PET Findings
The [18F]-dopa activity ratios for the putamen and the right
caudate nucleus were significantly reduced in individuals with SN hyperechogenicity
compared with the controls (Table 1
and Figure 2), although controls
were older and were therefore supposed to have a lower [18F]-dopa
uptake because of age-related nigral cell loss. In addition, the median putamen
and caudate Ki values were lower in individuals with enlarged areas of SN
hyperechogenicity than in controls (Table
1). Differences were significant for the putamen on both sides (Wilcoxon
test: left side, P = .04; right side, P = .03) but not for the caudate nucleus.
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[18F]-Dopa Ratios and Ki Values for the Caudate Nucleus
and Putamen of Individuals With a Hyperechogenic Substantia Nigra Area Greater
Than 0.25 cm2 and Control Individuals*
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Figure 2. Fluorine 18-dopa ([18F]-dopa)
activity ratios as measured by positron emission tomography in the caudate
nucleus and putamen of subjects with a hyperechogenic substantia nigra area
greater than 0.25 cm2 (SN+) and control subjects (CO). Median values
(25th percentile and 75th percentile) are also presented. The Wilcoxon matched
pair test showed a significant difference between CO and SN+ groups for both
the caudate nucleus and putamen on either side.
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Motor and Cognitive Examinations
No significant differences between controls and individuals with more
extended areas of SN hyperechogenicity were detected on pegboard and finger-tapping
tests (Wilcoxon test: P>.05) or regarding cognitive
functioning, problem solving, verbal memory, or attention (Wilcoxon test: P>.05).
POSTMORTEM ANALYSIS OF THE SN AND CORRELATION OF SN ECHOGENICITY WITH
TRACE METAL CONTENT AND RELATION TO HISTOLOGICAL PARAMETERS
Sonographic examination of the SN in the 20 postmortem brains revealed
a median extension of the hyperechogenic signals originating from the SN of
0.18 cm2(range, 0.11-0.25 cm2; left side, 0.17 cm2[range, 0.11-0.23 cm2]; right side, 0.18 cm2[range,
0.11-0.26 cm2]). In 3 brains the extension of hyperechogenic signals
was much higher than the threshold level of 0.25 cm2 (range, 0.30-0.32
cm2); in another 3 brains it was close to this threshold (range,
0.24-0.27 cm2). The higher frequency of the ultrasound probe results
in a higher spatial resolution and, consequently, slightly larger hyperechogenic
SN areas compared with the transcranial findings. Analysis of the trace metal
and calcium tissue levels of the SN with the extent of echogenic signals of
the SN showed a positive correlation for iron (Spearman rank correlation: R = 0.57; P = .007). Subjects
with more extended hyperechogenic signals at the SN had higher iron levels
than those with less echogenic SNs (Figure
3). No correlation was found for copper (R
= 0.34; P = .13), magnesium (R = 0.31; P = .18), zinc (R = 0.28; P = .21), or calcium (R = 0.43; P = .06).
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Figure 3. Correlation between substantia
nigra (SN) iron level (given as micrograms per gram of dry-weight SN tissue)
and area of hyperechogenic signals originating from the SN in 20 postmortem
brains. The figure represents a regression analysis and demonstrates that
SN hyperechogenicity is related to increased iron level (regression
analysis: R = 0.57; F = 8.59; P = .008). The
patient with an intense iron stain and Lewy bodies in the SN is marked with an asterisk.
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Histological examination of the SN revealed increased iron staining
in subjects with higher iron levels and larger areas of SN hyperechogenicity
(Figure 4A and B). In one subject
(age 51 years) with a large hyperechogenic SN area (0.3 cm2) and
a high SN iron level (752 ppm), histological analysis revealed Lewy bodies
in the locus coeruleus (Figure 4C) and SN. Although -synuclein and ubiquitin immunostaining showed several
Lewy bodies in the SN (Figure 4D
and 4E), they were even more numerous in the locus coeruleus. Evidence of
active cell loss was seen including the presence of extraneuronal melanin
and a slight gliosis. Results of the AT8 immunostaining were normal. No statement
regarding a selective reduction of pigmented neurons in the SN could be made
because no quantitative morphometric evaluation of the SN was performed. This
patient did not have PD or any symptoms attributed to diffuse Lewy body disease17 during his lifetime; therefore, a case of incidental
Lewy body disease might be postulated. In no other patient were we able to
identify -synuclein-positive Lewy bodies in the SN or in any other
brain area. In 3 cases, occasional -positive nerve cells and neurites
in the SN and locus coeruleus were seen. In an additional subject, numerous
senile plaques were identified in cortical areas and the hippocampus region.
The other cases revealed no major gross or histological changes.
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Figure 4. A, Substantia nigra with moderate
iron deposits (arrows) (Prussian blue stain, original magnification x200).
B, Substantia nigra with marked increase of iron, either diffuse or globular
(Prussian blue stain, original magnification x 200). C, Locus coeruleus
with occasional Lewy bodies (arrow) and numerous Lewy neurites. In addition,
a mild gliosis and free neuromelanin can be seen (-synuclein antibodies
[peroxidase antiperoxidase method], original magnification x250). D
and E, Substantia nigra with intracellular Lewy bodies (D, Nissl stain with
cresyl violet, original magnification x400. E, -Synuclein antibodies,
original magnification x450).
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COMMENT
Increased echogenicity of the SN is the characteristic ultrasound feature
of PD. Our findings indicate that the same echo pattern of the SN detected
in young healthy subjects may be associated with an impairment of the nigrostriatal
system as revealed by PET. Because the striatal [18F]-dopa uptake
is related to the number and metabolism of the nigral dopaminergic neurons,18 a reduced [18F]-dopa tracer uptake in
subjects with SN hyperechogenicity reflects nigral cell damage or a preexisting
reduced cell count. These findings corroborate the data from our pilot study.3 However, subjects included in the present study were
even younger. Both the echogenic SN sonographic phenotype and nigral dysfunction
can therefore be depicted at a young age. Despite the reduction in striatal
[18F]-dopa uptake, results of neurological and neuropsychological
examinations of the young subjects in the present study were normal.
Our data do not indicate that subjects with SN hyperechogenicity and
reduced [18F]-dopa uptake have preclinical PD because it is unknown
whether nigral injury will continue in some of these subjects in the future.
However, it may be tempting to consider SN hyperechogenicity in healthy adults
to represent a susceptibility marker for nigral injury because of the similarity
of the echo feature compared with PD and the association with an altered nigral
function disclosed by [18F]-dopa PET studies.
Increased echogenicity of the SN may be associated with higher tissue
iron levels, as seen in the postmortem examination. The finding of a correlation
between tissue iron content and echogenicity is supported by an animal experiment
revealing a dose-dependent increase in SN echogenicity after the stereotactic
injection of various concentrations of iron into the SN.10
Increased iron content may explain not only the increase in echogenicity but
also nigral cell injury as demonstrated by PET findings.19
From in vitro and in vivo experiments, it is known that iron may catalyze
free radical formation, leading to an impairment of cellular function by a
cascade of events including damage to the mitochondrial electron transport
system, the induction of proteases, and increased membrane lipid peroxidation.6-8,20-22
However, increased iron content alone cannot be the reason for the observed
increased SN echogenicity. Other brain structures with physiologically high
amounts of iron, such as the globus pallidus or red nucleus, usually appear
as unechogenic or slightly echogenic structures on TCS.4
Furthermore, the physiologically iron-rich SN normally reflects only a slightly
echogenic signal. Therefore, factors such as iron-binding proteins may be
important in creating increased SN echogenicity.
Additionally, one postmortem study demonstrated an increased SN echogenicity,
high SN iron levels, and Lewy bodies in the SN and locus coeruleus, classifying
this case as one of incidental Lewy body disease.23
This single-case observation of an association among SN hyperechogenicity,
iron accumulation, and Lewy body formation must be replicated and confirmed
in a larger series, particularly because it contrasts the findings of Dexter
et al,24 who reported normal SN iron levels
in patients with incidental Lewy body disease.
The prevalence rate of subjects with SN hyperechogenicity is similar
to that of incidental Lewy body disease,25-26
which is suggested to be the preclinical form of PD disclosed only by histopathological
examinations.27 However, the prevalence rate
of 9% for the phenotype of SN hyperechogenicity is much greater than the estimated
risk of PD.28 Therefore, SN hyperechogenicity,
which may be related to increased iron content, might be only 1 of several
factors playing a role in the initiation of neuronal loss in the SN. Other
factors such as endotoxins or exotoxins29-30
are probably necessary to induce or accelerate the degenerative process leading
to clinical PD. According to the differences in the prevalence rates, it is
clear that if at all, only a minority of subjects with SN hyperechogenicity
will proceed to PD. However, recent findings provide evidence of an association
between SN hyperechogenicity and motor impairment in elderly patients, indicating
that the factors causing this echo feature may gain functional relevance during
a patient's lifetime. In a cross-sectional study including 93 subjects older
than 60 years without prediagnosed extrapyramidal disorders, subjects with
more extended hyperechogenic signals at the SN showed a more severe slowing
of motor function even though most of them did not fulfill the diagnostic
criteria for PD.31
Our findings suggest that an increase in SN echogenicity, which appears
to be related to an increase in tissue iron content, may point toward a susceptibility
to nigrostriatal injury. This pattern of SN hyperechogenicity, similar to
that found in PD, can be detected early in life. To further elucidate the
significance of this finding and the relationship between SN hyperechogenicity
and PD, follow-up studies with PET should clarify whether the functional impairment
of the nigrostriatal system will progress in any of our subjects.
AUTHOR INFORMATION
Accepted for publication August 21, 2001.
This study was supported by the Deutsche Forschungsgemeinschaft BE 1774/4-1
and Siemens AG, Erlangen, Germany; Orion Pharma GmbH, Hamburg, Germany; Schering
Deutschland GmbH, Berlin, Germany; and SmithKline Beecham, Munich, Germany.
We gratefully acknowledge K. V. Toyka, MD, and P. Riederer, PhD, for
their continuous support, and W.-D. Rausch, PhD, for providing the trace metal
analyses.
Corresponding author and reprints: Daniela Berg, MD, Department of
Neurology, University of Würzburg, Josef-Schneider-Str 11, 97080 Würzburg,
Germany (e-mail: daniela.berg{at}mail.uni-wuerzburg.de).
From the Department of Neurology (Drs Berg and Reiners), Division of
Neuropathology (Drs Roggendorf and Klein), Institute for Forensic Medicine
(Dr Tatschner), and Department of Psychiatry (Dr Gerlach), Bayerische Julius-Maximilians-Universität
Würzburg, Würzburg, Germany, the Department of Neurology, University
of Homburg, Saar, Germany (Dr Becker and Mrs Schröder), the Department
of Neuropsychology, University of Regensburg, Regensburg, Germany (Drs Tucha
and Lange and Mr Preier), and PET-Zentrum Mainz, University of Mainz, Mainz,
Germany (Dr Benz).
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