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Diminished striatal [123I]iodobenzovesamicol binding in idiopathic cervical dystonia.

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Diminished Striatal
[123I]Iodobenzovesamicol
Binding in Idiopathic
Cervical Dystonia
Roger L. Albin, MD,1,2 Donna Cross, BSE,3,4
Wayne T. Cornblath, MD,2,5 John A. Wald, MD,2
Kristine Wernette, MSN,2,6 Kirk A. Frey, MD, PhD,2,6
and Satoshi Minoshima, MD, PhD4
Striatal dysfunction is thought to underlie many dystonias. We used [123I]iodobenzovesamicol single-photon
emission computed tomography imaging to determine
the density of cholinergic terminals in the striatum and
other brain regions in 13 subjects with idiopathic cervical
dystonia. Striatal [131I]iodobenzovesamicol binding was
reduced. These results support a role for striatal dysfunction in idiopathic dystonias and suggest diminished striatal cholinergic interneuron density in cervical dystonia.
Ann Neurol 2003;53:528 –532
From the 1Geriatrics Research, Education, and Clinical Center, Ann
Arbor VAMC; 2Department of Neurology and 3Neuroscience Graduate Program, University of Michigan, Ann Arbor; 4Department of
Radiology, University of Washington, Seattle; and Departments of
5
Opthalmology and 6Radiology, University of Michigan, Ann Arbor, MI.
Received Sep 6, 2002, and in revised form Dec 13. Accepted for
publication Dec 16, 2002.
Address correspondence to Dr Albin, Neuroscience Laboratory
Building, 4412D Kresge III, 200 Zina Pitcher Place, Ann Arbor,
MI 41809-0585.
E-mail: ralbin@umich.edu
This article is a US Government work and, as such, is in the public domain in the United States of America.
528
Published 2003 by Wiley-Liss, Inc.
Dystonias are a class of involuntary movements characterized by sustained postures of affected muscle
groups, often with a torsional or rotatory component.
Dystonia may be secondary to an identifiable pathological process involving the nervous system or idiopathic.
The pathophysiology of dystonia is unknown. Pathological examination of primary dystonias has been unrevealing.1 In secondary dystonias due to focal brain
lesions, the putamen is the most common site of brain
injury, though thalamic and brainstem lesions are associated also with dystonia.2–5 The loci responsible for
some forms of inherited generalized dystonia are
known. Dominantly inherited dopa-responsive dystonia (DRD; DYT5; Segawa’s syndrome) is caused by
mutations in GTP cyclohydrolase I, the rate limiting
enzyme in synthesis of tetrahydrobiopterin, a necessary
cofactor for tyrosine hydroxylase activity.6 Recessive
DRD is associated with mutations in tyrosine hydroxylase itself.6 The more common childhood or
adolescent-onset idiopathic torsion dystonia (ITD;
DYT1), a dominantly inherited disorder with incomplete penetrance, is caused by mutations in the torsinA
gene, a probable ATPase chaperone protein, which is
expressed at high levels in substantia nigra dopaminergic neurons.6 The association of putamenal injury with
secondary dystonia and the existence of dopamine synthesis abnormalities in DRD indicate that abnormalities of basal ganglia function underlie some forms of
dystonia and lead to the suggestion that most forms of
dystonia result from basal ganglia dysfunction. Perlmutter’s group published imaging data consistent with
putamenal abnormalities in idiopathic dystonia.7,8
Some evidence suggests that dystonia results from
abnormal sensorimotor coordination at the level of the
neocortex as a downstream effect of striatal dysfunction
(reviewed in Tamburin and colleagues).1,9 Some functional imaging evidence indicates abnormal sensorimotor processing in dystonias.10,11 Striatal cholinergic interneurons are suggested to mediate some forms of
sensorimotor integration, raising the possibility that
striatal cholinergic interneuron abnormalities could underlie dystonia.12 We evaluated this possibility with
[123I]iodobenzovesamicol (IBVM) single-photon emission computed tomography (SPECT) imaging, a
method that gives an estimate of the density of cholinergic nerve terminals.
Subjects and Methods
Subjects
Thirteen subjects with idiopathic cervical dystonia were recruited from the Botulinum Toxin Clinic at the University
of Michigan. The mean age was 53 years (range, 41–71
years). There were 10 female subjects and 3 male subjects.
The mean duration of cervical dystonia was 7.3 years (range,
1–21 years). Two subjects had associated blepharospasm and
one had associated oromandibular dystonia. Two subjects
also had essential tremor. Seven subjects were taking no
medications for treatment of dystonia, but one subject took
carbidopa/L-dopa, one took gabapentin, one took propranolol, one took trihexyphenidyl and clonazepam, and one took
pimozide. Results from cervical dystonia subjects were compared with results from 15 age-matched control subjects
without neurological disease.
Tracer Chemistry
IBVM was prepared by oxidative radioiodination of the respective (⫺)-5-tributylin precursor, with specific activity
greater than 1.11 ⫻ 109MBq mmol⫺1 (30,000Ci/mmol)
and was injected intravenously as a 370MBq (10mCi) dose.
To minimize iodine uptake in the thyroid, we gave each subject oral Lugol’s solution (1 drop three times a day) for 1 day
before and 3 days after scanning. Bowel radiation exposure
was minimized by administration of a laxative (Dulcolax;
Ciba-Geigy, Summit, NJ), 1 day after scanning.
Single-Photon Emission Computed Tomography
Studies and Image Analysis
IBVM-SPECT was performed as described previously.13,14
[123I]IBVM images were collected sequentially over the first
4.5 hours after injection and for 1 hour on the following
day. Three sets of images were collected in each subject without measuring the arterial tracer input function: 0 to 30
minutes for transport index and anatomy, 3 hours to 3 hours
30 minutes for striatum and cortical anatomy, and 22 hours
to 23 hours for binding index. Reconstructed spatial resolution of the SPECT tomograph (Prism 3000; Picker International, Cleveland, OH) was 13.5mm (full-width at halfmaximum) in the center of the transverse plane and axially.
SPECT image analysis was performed as described previously.14 Head motion was corrected using fiducial markers in
each set of frames. Frames obtained on the first and second
days and coregistered to the same orientation using an algorithm based on image similarity.15 Predefined volumes of interest were used as described previously and included frontal
association cortex, parietal association cortex, occipital association cortex, temporal association cortex, anterior cingulate
cortex, posterior cingulate cortex, primary visual cortex, hippocampus, caudate, putamen, total striatum, pons, and cerebellum.14 Activities were averaged (area weighed) within
each VOI. VOI activities were measured separately for both
hemispheres and averaged together for subsequent analysis.
All subjects had zonal [123I]IBVM binding indices determined as the ratio of regional activity to cerebellar activity as
measured from the brain images made 22 hours after injection.
Statistical Analysis
For overall comparison between dystonic and control groups,
three-dimensional stereotaxic surface projection extracted
data sets normalized to cerebellar activity were compared
with analysis of variance with repeated measures (regions).
Regions were compared across groups with individual Student’s t tests. To correct for multiple comparisons, we performed a Bonferroni adjustment to set a threshold of p value
less than 0.05. After the analysis by cerebellar normalization,
we found significant changes in the striatum (see below) and
performed an additional analysis with global normalization.
Global activity was calculated by averaging gray matter pixels
over the entire brain in the three-dimensional stereotaxic surface projection extracted format.
Results
SPECT measurements with cerebellar normalization
for control and cervical dystonia groups are presented
in the Table. There was evidence of widespread reductions in IBVM binding with significant decrements in the putamen and total striatum (see Table,
Fig 1). Overall, between-subject difference was significant at F ⫽ 9.953 ( p ⫽ 0.004). On individual comparisons between regions, the decrement in the caudate nucleus approached significance, and the striatal
(caudate and putamen) and putamen decrement were
significant ( p ⬍ 0.05). There were no significant regional differences in cerebral blood flow between
groups (Fig 2). With use of global normalization,
there was a significant difference between the two
groups (F ⫽ 4.132; p ⫽ 0.05). Individual regional
comparisons showed diminished striatal (⫺12%; p ⬍
0.05) and increased cerebellar (⫹15%; p ⫽ 0.02)
IBVM binding.
Discussion
[123I]Iodobenzovesamicol binds to the vesicular acetylcholine transporter (VAChT), the protein responsible
for pumping acetylcholine into synaptic vesicles.
VAChT is a specific marker of cholinergic terminals
and is thought to be a stable anatomical marker of cholinergic terminal density. Unlike other cholinergic terminal markers, such as the choline transporter,
VAChT expression is not regulated by disease-induced
alterations in cholinergic neurotransmission or drugs
that affect cholinergic neurotransmission.16 Similar
lack of pharmacological regulation is documented well
in studies of the type 2 vesicular monoamine transporter (VMAT2), the homologous protein responsible
for pumping monoamines into synaptic vesicles.17
Our results suggest a deficit in cholinergic nerve terminals in several brain regions, though in the primary
analysis our results attain significance only in the putamen and total striatum. The Bonferroni correction
used to compensate for multiple comparisons, however,
is a conservative method that may result in underestimates of significance. The secondary analysis, using
global normalization, is consistent also with diminished
striatal IBVM binding. Our methods do not allow determination of absolute, but only relative, IBVM binding. The use of cerebellar normalization assumes normal cerebellar IBVM binding. In a previous study, the
cerebellar normalization method described accurately
the pattern of brain cholinergic deficits in Alzheimer’s
and Parkinson’s disease.14 Results of the global normalization analysis are consistent with reduced striatal
Albin et al: [123I]IBVM SPECT in Dystonia
529
Table. [123I]IBVM Binding, Ratio of Regional Binding to Cerebellar Binding
Region
Frontal
Association
Cortex
Parietal
Association
Cortex
Occipital
Association
Cortex
Primary
Visual
Cortex
Temporal
Association
Cortex
Anterior
Cingulate
Cortex
Posterior
Cingulate
Cortex
CONT
SD
DYS
SD
Difference (%)
1.0005
0.2051
0.8277
0.1348
⫺17
0.7212
0.1504
0.6514
0.1011
⫺10
0.6945
0.1660
0.6148
0.0917
⫺11
0.7183
0.1794
0.6721
0.0926
⫺6
0.9964
0.1847
0.8727
0.1260
⫺12
1.5609
0.3567
1.2426
0.2471
⫺20
0.9715
0.2092
0.8193
0.1223
⫺16
After correction for multiple comparisons with Bonferroni correction, differences between control and torticollis (DYS) putamen and striatum
are significant.
CONT ⫽ control; SD ⫽ standard deviation; DYS ⫽ torticollis.
Fig 1. Summed delayed (22 hour) [123I]iodobenzovesamicol (IBVM) single-photon emission computed tomography (SPECT) images
(representing vesicular acetylcholine transporter [VAChT] binding) for torticollis and control subjects. Reference (REF) row shows
anatomical configuration of images. Normal and torticollis rows show [123I]IBVM binding to VAChT in control and torticollis
subjects, respectively. Reduction row images show subtraction of torticollis from control images. Data in normal and torticollis rows
represented as zonal binding indices, the ratio of regional binding to cerebellar binding. Scale is shown on left of color bar in lower
right-hand corner. Reduction row data are represented as Z-scores, the number of standard deviations of torticollis regional means
from control regional means (Scale shown on right of color bar). Arrows show striatal complex.
IBVM binding relative to both global brain IBVM binding and cerebellar IBVM binding. Because the literature
on secondary dystonia favors striatal lesions as the ana-
530
Annals of Neurology
Vol 53
No 4
April 2003
tomical correlate of dystonia, our results are consistent
with the general idea that striatal dysfunction is a key
element of the pathophysiology of dystonia.
Hippocampal
Formation
and Amygdala
1.7060
0.3310
1.4896
0.5209
⫺13
Caudate
Putamen
Striatum
Thalamus
Sensorimotor
Cortex
6.8145
1.3142
5.1247
1.4800
⫺25
5.1132
0.9789
3.8835
0.9986
⫺24
5.3540
1.0167
4.0591
1.0589
⫺24
3.8844
0.9720
3.1822
0.7296
⫺18
1.1452
0.2588
0.9306
0.1614
⫺19
Pons
1.3696
0.2123
1.2391
0.2372
⫺10
Fig 2. Summed early (0 –30 minute) [123I]iodobenzovesamicol (IBVM) single-photon emission computed tomography (SPECT) images (representing perfusion) for torticollis and control subjects. REF, normal, torticollis, and reduction rows identical to those in
Figure 1. Color bar is also the same as for Figure 1. There are no differences in perfusion between control and torticollis subjects.
Although cholinergic interneurons comprise a small
fraction of all striatal neurons, they have extensive ramifications and striatal expression of cholinergic markers
such as VAChT is the highest in the central nervous
system. Experimental animal studies, human postmortem studies, and imaging studies of human neurodegenerations involving cholinergic pathways indicate
that VAChT binding is an index of cholinergic neuron
integrity.14,16,18 Diminished striatal IBVM binding
suggests a decrement in the density of striatal cholinergic interneurons.
Striatal cholinergic interneurons are identified with
the striatal tonically active neurons that respond to behavioral sensorimotor conditioning.12,19,20 During
conditioning, the activities of widely dispersed tonically
active neurons become synchronized and are likely to
Albin et al: [123I]IBVM SPECT in Dystonia
531
influence a large volume of surrounding striatal neurons.13,19,20 Blazquez and colleagues suggested recently
that striatal cholinergic interneurons signal the probability that a stimulus will evoke a behavioral response.20 It is attractive to think that dysfunction of
striatal cholinergic interneurons, which respond to context specific sensory cues, could have something to do
with dystonic phenomena.
Our finding requires confirmation with quantitative
methods. Whether deficit of striatal cholinergic neurons is the primary cause of cause of dystonia or a
manifestation of another underlying process requires
further investigation.
This work was supported by PHS NS15655 (K.A.F., R.L.A., K.W.,
S.M.), DOE-DE-FG02-87ER60561 (K.A.F.), and a VA Merit Review Grant.
We thank the subjects for their willingness to participate in these
studies.
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April 2003
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