Diminished striatal [123I]iodobenzovesamicol binding in idiopathic cervical dystonia.код для вставкиСкачать
8. Scerrati M, Roselli R, Iacoangeli M, et al. Prognostic factors in low grade (WHO grade II) gliomas of the cerebral hemispheres: the role of surgery. J Neurol Neurosurg Psychiatry 1996;61: 291–296. 9. Keles GE, Lamborn KR, Berger MS. Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J Neurosurg 2001;95:735–745. 10. Recht LD, Lew R, Smith TW. Suspected low-grade glioma: is deferring treatment safe?. Ann Neurol 1992;31:431– 436. 11. Cairncross JG. Understanding low-grade glioma: a decade of progress. Neurology 2000;54:1402–1403. 12. Olson JD, Riedel E, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology 2000;54:1442–1448. 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: firstname.lastname@example.org 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. References 1. Dauer WT, Burke RE, Greene P, Fahn S. Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 1998;121:547–560. 2. Kostic VS, Stojanovic-Svetel M, Kacar A. Symptomatic dystonias associated with structural brain lesions: report of 16 cases. Can J Neurol Sci 1996;20:53–56. 3. Marsden CD, Obeso JA, Zarranz JJ. The anatomic basis of symptomatic dystonia. Brain 1985;108:463– 483. 4. Obeso JA, Gimenez-Roldan S. Clinicopathological correlation in symptomatic dystonia. Adv Neurol 1988;50:113–122. 5. Pettigrew LC, Jankovic J. Hemidystonia: a report of 22 cases and a review of the literature. J Neurol Neurosurg Psychiatry 1985;48:650 – 657. 6. Klein C, Ozelius LJ. Dystonia: clinical features, genetics, and treatment. 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