Tourette syndrome: Prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding

Science

Volumn 273, Issue 5279, 1996, Pages 1225-1227

  Wolf, Steven S ^a   Jones, Douglas W ^a   Knable, Michael B ^a   Gorey, Julia G ^a   Lee, Kan Sam ^a   Hyde, Thomas M ^a   Coppola, Richard ^a   Weinberger, Daniel R ^a  

^a NATIONAL INSTITUTE OF MENTAL HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DOPAMINE 2 RECEPTOR;

ADULT; ARTICLE; AUTOSOMAL DOMINANT INHERITANCE; CAUDATE NUCLEUS; CLINICAL ARTICLE; CORPUS STRIATUM; DISEASE SEVERITY; FEMALE; GILLES DE LA TOURETTE SYNDROME; HUMAN; MALE; MONOZYGOTIC TWINS; PHENOTYPE; PRIORITY JOURNAL; RECEPTOR BINDING; RECEPTOR DENSITY; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY;

EID: 0029834998     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.273.5279.1225     Document Type: Article

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24. Twin pairs were solicited through the national newsletter of the Tourette Syndrome Association. Of nearly 100 responding twin pairs, 5 pairs fulfilled all selection criteria (adult, monozygotic, neuroleptic-free. and discordant for symptom severity). Complete matching of 19 red cell antigens (National Reference Laboratory for Blood Serology, American Red Cross, Rockville, MD) confirmed monozygosity with a probability of >97% [F. Vogel and A. G. Motulsky, Human Genetics (Springer-Verlag, New York, 1986) pp. 578-585]. Five participants were neuroleptic-naive, three were neuroleptic-free for 3 years or more, and two discontinued low dosages of pimozide (1 mg/day) and haloperidol (1 mg/day). respectively, 6 weeks before the study. Diagnosis of TS followed published guidelines [S. Fahn et al., Arch. Neurol. 50, 1013 (1993)]. Patients were rated for symptom severity with an aggregate clinical score calculated as the sum of the following complementary scales: Shapiro Symptom Check List, Yale Global Tic Severity Rating Scale, and Yale Tic Count (performed immediately before SPECT scanning). Written informed consent was obtained from all participants under a protocol approved by the Institutional Review Board of the National Institute of Mental Health.
25. Twin pairs were solicited through the national newsletter of the Tourette Syndrome Association. Of nearly 100 responding twin pairs, 5 pairs fulfilled all selection criteria (adult, monozygotic, neuroleptic-free. and discordant for symptom severity). Complete matching of 19 red cell antigens (National Reference Laboratory for Blood Serology, American Red Cross, Rockville, MD) confirmed monozygosity with a probability of >97% [F. Vogel and A. G. Motulsky, Human Genetics (Springer-Verlag, New York, 1986) pp. 578-585]. Five participants were neuroleptic-naive, three were neuroleptic-free for 3 years or more, and two discontinued low dosages of pimozide (1 mg/day) and haloperidol (1 mg/day). respectively, 6 weeks before the study. Diagnosis of TS followed published guidelines [S. Fahn et al., Arch. Neurol. 50, 1013 (1993)]. Patients were rated for symptom severity with an aggregate clinical score calculated as the sum of the following complementary scales: Shapiro Symptom Check List, Yale Global Tic Severity Rating Scale, and Yale Tic Count (performed immediately before SPECT scanning). Written informed consent was obtained from all participants under a protocol approved by the Institutional Review Board of the National Institute of Mental Health.
26. H. F. Kung et al., J. Nucl. Med. 30, 88 (1989). Recent evidence indicates that IBZM also binds to D3 dopamine receptors (M. P. Kung, unpublished data). Although D3 receptor density is relatively low compared with that of D2 receptors in the regions we studied [A. M. Murray, H. L. Ryoo, E. Gurevich, J. N. Joyce, Proc. Natl. Acad. Sci. U.S.A. 91, 11271 (1994)], our measurements of IBZM binding may include some small fraction due to D3 receptor binding.
27. H. F. Kung et al., J. Nucl. Med. 30, 88 (1989). Recent evidence indicates that IBZM also binds to D3 dopamine receptors (M. P. Kung, unpublished data). Although D3 receptor density is relatively low compared with that of D2 receptors in the regions we studied [A. M. Murray, H. L. Ryoo, E. Gurevich, J. N. Joyce, Proc. Natl. Acad. Sci. U.S.A. 91, 11271 (1994)], our measurements of IBZM binding may include some small fraction due to D3 receptor binding.
28. 123I]IBZM was prepared [M.-P. Kung and H. F. Kung, J. Labelled Comps. Radiopharm. 27, 691 (1989)] and administered intravenously (mean dose: 5.27 ± 0.77 mCi). Multiple SPECT scans [CERASPECT; Digital Scintigraphics, Waltham, MA; full width at half-maximum (FWHM), 11.5 mm; 64 1.67-mm slices; 15 min per scan] began 15 min after injection and continued over 4 hours. Individual scans were coregistered in three orthogonal planes to templates created on the 4-hour time-averaged image. To define anatomical ROIs, we also coregistered volume magnetic resonance imaging (MRI) scans (GE 1.5T Signa; spoiled gradient recalled acquisition in steady state; repetition time, 24 ms; time to echo, 5 ms) with the time-averaged image. ROIs sampling the head of the caudate nucleus, the body of putamen, and the cerebellum were drawn on five contiguous transverse MRI slices and transferred to corresponding SPECT images. Activity concentration (cpm/ml) was measured for the volume encompassed by each set of ROIs, corrected for decay, and normalized to injected dose.
29. M. B. Knable et al., J. Nucl. Med. 36, 1216 (1995).
30. Individual caudate nucleus binding values by twin pair (more severe, less severe) were as follows: 1.51, 1.50; 1.67, 1.31; 1.12, 0.93; 1.19, 1.15; and 1.97, 1.34. Putamen values were as follows: 2.11, 2.77; 2.12, 2.32; 2.03, 1.60; 1.60, 1.43; and 2.27, 2.14.
31. 99mTc]HMPAO (mean dose: 14.9 ± 0.2 mCi). Attenuation-corrected scans were coregistered and analyzed as described (11) except that these data were normalized to the whole slice. Striatal blood flow measurements revealed no significant differences between more and less affected twins for either caudate nucleus (mean ± SEM: 90 ± 3 compared with 88 ± 4) or putamen (127 ± 2 compared with 128 ± 2) (Wilcoxon test, P - 0.69 for both).
32. 123I]IBZM binding was estimated from the midpoint of the linear portion in the integral method (12) and ranged from 75 to 125 min after injection. Within-pair concordance on this measure was high [unbiased intraclass correlation coefficient, ICC(U), = 0.94 for caudate nucleus, P < 0.0005; ICC(U) = 0.82 for putamen, P < 0.005] [J. J. Bartko and W. T. Carpenter Jr., J. Nerv. Ment Dis. 163, 307 (1976)].
33. A statistical power analysis revealed that, given our means and standard deviations for caudate nucleus IBZM binding data, a sample size of 33 persons in each group would be required for 90% power to observe a significant difference in a nontwin design. A similar analysis for the putamen data revealed that more than 9000 persons in each group would be required for this region.
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36. We gratefully acknowledge the assistance of E. Watsky, H. Leonard, and K. Rickler. This work was partially funded through an award from the Tourette Syndrome Association (T.M.H.).