J Neurol (2000) 247 : 514–520
© Steinkopff Verlag 2000
ORIGINAL COMMUNICATION
Kirsten R. Müller-Vahl Georg Berding Thomas Brücke Hans Kolbe Geerd J. Meyer Heinz Hundeshagen Reinhard Dengler Wolfram H. Knapp Hinderk M. Emrich
Dopamine transporter binding in Gilles de la Tourette syndrome
Received: 13 September 1999 Received in revised form: 24 January 2000 Accepted: 16 February 2000
Abstract Preliminary studies in patients with Gilles de la Tourette syndrome (TS) provided evidence of presynaptic dopaminergic dysfunction, demonstrating increased reuptake sites. Therefore we investigated striatal dopamine transporter binding in 12 TS patients and 9 control subjects using single photon emission computed tomography and 123I-labeled 2ß-carbomethoxy–3ß-(4iodophenyl)tropane. In TS patients we found significantly higher relative striatal activity ratios (mean ±SD 12.33±3.58) than in controls (9.36±1.35, P< 0.05). Only five patients, however, showed striatum/occipital cortex ratios more than 2 SD above the normal means. Seven patients had activity ratios within the average ratio of the control group plus 2 SD. Regarding the relationship between clinical parameters and striatum/occipital cortex ratios, we found an association between binding
K. R. Müller-Vahl () · H. M. Emrich Department of Clinical Psychiatry and Psychotherapy, Medical School of Hanover, Carl-Neuberg-Strasse 1, 30623 Hanover, Germany Tel.: +49–5 11–5 32 31 10, Fax: +49–5 11–5 32 31 15 e-mail:
[email protected] K. R. Müller-Vahl · H. Kolbe · R. Dengler Department of Neurology, Medical School of Hanover, Carl-Neuberg-Strasse 1, 30623 Hanover, Germany G. Berding · G.J. Meyer · H. Hundeshagen · W.H. Knapp Department of Nuclear Medicine, Medical School of Hanover, Carl-Neuberg-Strasse 1, 30623 Hanover, Germany T. Brücke University Neurology Clinic and Clinic of Nuclear Medicine, Vienna, Austria
Introduction Gilles de la Tourette syndrome (TS) is a complex neuropsychiatric spectrum disorder characterized by motor and vocal tics and a variety of associated behavioral disorders. The biochemical cause is unknown, but there is substantial evidence that the dopaminergic system is pathophysiologically involved [19]. It is well known that dopamine-blocking drugs reduce tics [24], and that dopaminergic agents enhance them [10]. The dopamine metabolite homovanillic acid has been found to be reduced
ratios and “self-injurious behavior” and “lack of impulse control.” This study corroborates previous data suggesting an involvement of the dopaminergic system in TS pathology. Our results demonstrate that an increase in dopamine transporter capacity is a possible but not a necessary alteration, and which appears more likely when self-injurious behavior and lack of impulse control are associated. Key words Dopamine transporter · 2ß-Carbomethoxy–3ß-(4iodophenyl)tropane single photon emission computed tomography · Gilles de la Tourette syndrome · Tics
in the cerebrospinal fluid of TS patients [3, 6]. Postmortem studies demonstrate increased [3H]mazindol binding to the dopamine transporter [25]. Neuroimaging studies using positron-emission tomography (PET), [18F]dopa [11C]raclopride PET, and [123I]iodo–6-methoxybenzaminde single photon emission computed tomography (SPECT) failed to demonstrate any dysfunction of the dopaminergic system, either in presynaptic dopaminergic terminals or in postsynaptic dopamine D2 receptor binding [9, 17, 27]. The cocaine analog 123I–2β-carbomethoxy–3β-(4iodophenyl)tropane (123I-β-CIT) has been found to have a
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made according to DSM-IV criteria. For diagnosing obsessive-compulsive behavior (OCB) and self-injurious behavior we used a structured questionnaire asking about obsessions and compulsions such as checking, ordering, doing things just right, counting, rituals, washing, and doing things an exact number of times, and about self-injurious behavior such as head banging, hitting or biting oneself, and more serious injuries. Because it is well known that TS patients often exhibit obsessive-compulsive symptoms but do not meet DSMIV criteria for obsessive-compulsive disorder [7], we preferred to use the term OCB instead. Table 1 summarizes clinical details such as disease severity according to the STSS, tic frequency according to the Tourette Syndrome Global Scale – subdivided into simple motor tics (SMT), complex motor tics (CMT), simple vocal tics (SVT), and complex vocal tics (CVT) [11] – associated behavioral disorders, disease duration, and kind of medication are. Physical and neurological examination, routine blood and urine laboratory tests, and magnetic resonance imaging were carried out to exclude other neurological and psychiatric disorders. Informed written consent was obtained from each individual. We compared our findings with results obtained from nine agematched, drug-free healthy control subjects (six men, three women; mean age 48 years, range 26–72).
high affinity to the dopamine and serotonin transporter, low nonspecific binding, and slow brain kinetics [15]. Using 123I-ß-CIT and SPECT, Malison et al. [16] found an increase in dopamine reuptake sites in five TS patients. These results corroborated postmortem findings [25] and results from a previous PET study with 11C-WIN 35.428 [29], suggesting a dysregulation in presynaptic dopamine function in TS. However, two recent 123I-ß-CIT SPECT studies found no change in dopamine reuptake site density in the basal ganglia [13, 20]. The aim of the present study was to extend the data base regarding the function of dopamine reuptake sites in patients suffering from TS, particularly with regard to individual clinical symptoms. We investigated a group of TS patients and normal control subjects using 123I-ß-CITSPECT. Methods and materials
Radiopharmaceuticals
Subjects
[123I]2-ß-Carbomethoxy–3-β-(4-iodophenyl)-tropane (123I-ß-CIT) was produced at the Forschungszentrum Seibersdorf, Austria, as described by Neumeyer et al. [18] with some modifications [2]. Radiochemical purity and specific activity were higher than 95 % and 5000 Ci/mmol, respectively. A mean activity of 162 MBq (range 97–205) 123I-β-CIT was administered to subjects intravenously after thyroid blockade with perchlorate.
We studied 12 consecutive patients (all men; mean age 35.2 years, range 24–64 years) suffering from TS according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The mean severity of the disease was 3.4 (range 2–5) on the Shapiro Tourette Syndrome Severity Scale (STSS) [23]. At the time of investigation two patients were receiving medication in the form of dopamine-blocking drugs (neuroleptics), two patients with serotonin reuptake inhibitors (SRI), two patients had a combined therapy (neuroleptics and SRI), and six had remained drug free for at least 5 months before entering the study (Table 1). The diagnoses of comorbid attention deficit hyperactivity disorder, addiction, lack of impulse control, anxiety, and depression were
Data acquisition and analysis All control subjects were studied at the University Neurology Clinic and Clinic for Nuclear Medicine in Vienna, Austria. All TS patients
Table 1 Clinical details of patients suffering from TS. Tics were rated on the Tourette Syndrome Global Scale (SMT simple motor tics, CMT complex motor tics, SVT simple vocal tics, CVT complex vocal tics; 0–5: 0 none, 1 rarely, 2 occasionally, 3 frequently, 4 almost always, 5 always); obsessive compulsive behavior (OCB) was rated on a clinically obtained severity scale (0–3: 0 none, 1 mild, 2 moderate, 3 marked or severe). (STSS Shapiro Tourette Syndrome Severity Scale, ADHD attention deficit hyperactivity disorder, NL neuroleptics, SRI serotonin reuptake inhibitor, Med medication, SIB self-injurious behavior, Add addiction, LIC lack of impulse control, Anx anxiety, Dep depression) Patient no.
Sex
Age Duration (years) of disease (years)
Med
STSS SMT
CMT SVT
CVT
ADHD
OCB SIB
Add
LIC
Anx
Dep
1 2 3 4 5 6 7
M M M M M M M
31 25 64 24 30 52 32
13 22 53 19 24 40 14
3 4 4 5 4 3 2
1 4 3 5 4 3 2
2 1 2 2 3 2 1
1 3 3 4 3 2 2
1 1 2 3 2 1 1
– + – – – + +
3 1 2 2 2 2 3
+ + + – + + –
– – – – + – –
+ + – + + + –
+ + – – + + +
– + + – + + –
8 9 10
M M M
24 28 44
14 11 38
2 4 4
3 2 4
1 1 1
2 2 3
0 3 2
– – –
2 3 2
+ + –
+ – –
+ + –
+ + –
+ + –
11 12
M M
30 38
22 31
NL – – – NL – NL, SRI – SRI NL, SRI – SRI
2 3
2 3
1 2
2 2
2 1
+ –
2 3
– +
– +
– +
+ +
– +
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were investigated at the Medical School of Hanover, Germany. In both groups the same type of imaging device was used for SPECT (Siemens Multispect 3, equipped with medium-energy collimators, spatial resolution of 12–13 mm full-width at half-maximum). Acquisition protocols and means of data analysis were identical. To guarantee comparability of measurements at the two centers, strict quality control of the imaging devices was carried out. Selection of energy channel was controlled at daily and homogeneity at weekly intervals. The upper tolerance limit for the integral inhomogeneity was 6 %. Fine and coarse tuning were performed if necessary. For image acquisition the subject’s head was fixed in a head holder with the canthomeatal line perpendicular to the rotation axis. With a mean delay of 24 h and 43 min postinjection (range 20 h 30 min–28 h 9 min) 180 frames (60 frames/head) were acquired over 360°. A frame duration of 40 s and a matrix size of 128×128 were selected (pixel size=3.56×3.56 mm2). Transaxial tomograms were reconstructed by filtered backprojection using a Butterworth filter with a cutoff at 0.55 Nyquist and an order of 20. Tomograms were corrected for photon attenuation employing Chang’s method with a coefficient of µ=0.12/cm [5]. For region of interest (ROI) analysis three consecutive slices with the maximum striatal uptake were added. Standardized ROIs were placed manually over caudate and putamen on each side and one reference ROI over the occipital cortex. Ratios of count densities between striatal and occipital regions were calculated. With these ratios putamen to caudate ratios and asymmetry index (AI)=[(right–left)×100]/[(right+left)×1/2] were determined in analogy to the method described by Seibyl et al. [22]. Statistical analysis The significance of differences in striatum to cortex ratios, age, and duration of the disease between either TS patients and normal controls or different subgroups of TS patients was assessed using Student’s t test for unpaired samples. The χ2 test was used to assess whether the incidence of different clinical scores differed significantly in patient subgroups with respect to their activity ratios. A P value lower than 0.05 was regarded as statistically significant.
Results The overall group of TS patients demonstrated significantly higher relative striatal activity than normal controls (P< 0.05). In controls the mean activity ratio between striatum (caudate and putamen) and occipital cortex (ST/OC) was 9.36±1.35 (range 7.28–11.14; Table 2). In TS patients
Table 3 Activity ratios of right and left side caudate/occipital cortex, putamen/occipital cortex and means in 12 patients with TS Caudate/occipital cortex Patient Right side Left side no.
Putamen/occipital cortex Right side Left side
Mean
1 2 3 4 5 6 7 8 9 10 11 12
14.18 13.90 9.19 8.88 7.89 10.60 9.64 17.06 18.68 11.75 11.01 12.84
14.68 13.45 8.45 8.74 7.50 11.37 9.94 17.65 19.14 12.01 11.62 13.46
13.68 13.84 8.38 8.95 7.27 12.05 9.54 18.28 20.20 11.44 11.69 14.15
16.03 13.13 8.75 8.60 7.74 12.10 10.29 19.07 19.29 11.93 12.37 13.81
14.81 12.93 7.49 8.52 7.10 10.72 10.28 16.17 18.38 12.93 11.42 13.03
the mean ST/OC ratio was 12.33±3.58 (range 7.50–19.14; Table 3, Fig. 1). Figure 2 shows SPECT images of a TS patient with increased striatal activity and a control subject exhibiting normal activity. The two groups also differed as well when the activity of striatum was distinguished as to the contributions of putamen and caudate nucleus ratios (P< 0.05; Table 4). There was, however, no difference in the mean putamen to caudate ratios (right and left side) in TS (right side 1.02±0.07, left side 1.07±0.07) and control group (right side 1.01±0.06, right side 1.03±0.08). The asymmetry index (caudate, putamen, and striatum) also showed no statistically significant difference (striatal asymmetry index in TS patients –0.43±5.66, striatal AI in normal controls 1.44±4.13), indicating that there was no group-specific preferential lateralization in striatal uptake (Table 4). However, only 5 of 12 TS patients had ST/OC ratios exceeding the average ratio of the control group by 2 SD
Table 2 Activity ratios of right and left side caudate/occipital cortex, putamen/occipital cortex and means in 9 normal control subjects Control no.
Sex
Age (years)
Caudate/occipital cortex Right side Left side
Putamen/occipital cortex Right side Left side
Mean
1 2 3 4 5 6 7 8 9
M F M M F F M M M
72 27 68 57 61 71 27 27 26
8.81 9.44 7.20 9.38 11.43 7.54 9.92 10.12 11.40
8.46 9.98 7.09 8.81 10.34 7.53 9.77 11.01 11.87
8.75 9.60 7.28 8.95 10.70 7.63 9.62 10.61 11.14
9.09 8.77 7.38 9.05 10.72 8.04 9.59 10.69 11.31
8.65 10.20 7.45 8.54 10.31 7.39 9.21 10.60 9.98
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Fig. 1 Striatum to occipital cortex ratios (ST/OC) in 9 control subjects (9.36±1.35, range 7.28–11.14) and 12 TS patients (12.33±3.58, range 7.50–19.14; P< 0.05). Mean values are plotted. Binding ratios for 7 of the 12 TS patients were within 2 SD of the normal means, and the ratios of the other 5 TS patients exceeded this range
(6.76–12.06; Fig. 1). The clinical data of these 5 patients were compared with those of the other 7 patients. Therefore for each patient a variety of clinical data were recorded: severity of the disease on the STSS, tic frequency on the Tourette Syndrome Global Scale (SMT, CMT, SVT, CVT), association with behavioral disorders such as attention deficit hyperactivity disorder, OCB, self-injurious behavior, addiction, lack of impulse control, anxiety, depression, disease duration, and kind of medication (Table 1). Each of these 14 clinical measures was assessed in relation to patients’ ST/OC ratios to examine whether clinical symptoms were associated with relative striatal activity. Therefore the group of TS patients was subdivided into two subgroups: one exhibiting ST/OC ratios exceeding the average of the control group plus 2 SD and one showing ST/OC ratios within 2 SD of the normal means. The duration of the disease was compared in these subgroups using unpaired Student’s t test. All other clinical data were analyzed in the two subgroups using the χ2 test. Therefore, 13 different scores corresponding to the clinical parameters were determined in each patient. In addition, for the 6 numeric scores two groups of similar size with high and low scores were formed: STSS (≤3/≥4), SMT (≤3/≥4), CMT (≤1/≥2), SVT (≤2/≥3), CVT (≤1/≥2), OCB (≤2/≥3). We found a significant association between activity ra-
Fig. 2 β-CIT SPECT. Left Increased relative striatal activity is illustrated in a TS patient (no. 9, ST/OC=19.14/1); right normal relative striatal activity is demonstrated in a control subject (no. 2, ST/OC=9.60/1)
Table 4 Mean activity ratios of caudate/occipital cortex (CD/OC), putamen/occipital cortex (PU/OC), putamen/occipital cortex (ST/OC), putamen caudate (PU/CD), and asymmetry index values in TS patients and controls (R right side, L left side)
TS Mean SD Controls Mean SD P (two-tailed)
CD/OC R
L
PU/OC R
L
ST/OC R+L
PU/CD R
L
Asymmetry index CD PU
12.46 3.89
12.76 3.82
12.14 3.33
11.98 3.44
12.33 3.58
1.02 0.07
1.07 0.07
–2.70 6.15
1.89 8.27
–0.43 5.66
9.47 1.48 < 0.05
9.40 1.31 < 0.05
9.43 1.59 < 0.05
9.15 1.22 < 0.05
9.36 1.35 < 0.05
1.01 0.06 n. s.
1.03 0.08 n. s.
0.44 5.07 n. s.
2.56 6.49 n. s.
1.44 4.13 n. s.
ST (CD+PU)
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tios (ST/OC) and the clinical measures “self-injurious behavior” (P< 0.05) and “lack of impulse control” (P< 0.05). All five patients with binding ratios greater than 2 SD of the normal means suffered from both self-injurious behavior and lack of impulse control. Three of the patients exhibiting binding ratios within normal means ±2 SD also suffered from self-injurious behavior and/or lack of impulse control while four did not. No association was found, however, between any other tested clinical feature and activity ratios (ST/OC; (P> 0.5, except for disease duration, P> 0.3). Discussion The aim of the present study was to lend further support to the postulation that TS is associated with changes in the function of dopamine reuptake sites. The results of our study provide evidence that there is a significant difference in striatal/occipital activity ratios between patients with TS and control subjects using 123I-β-CIT and SPECT. Furthermore, our data suggested that an increase in dopamine transporter capacity is more likely when “self-injurious behavior” and “lack of impulse control” are associated. β-CIT is a potent cocaine analog and has been shown to possess a high affinity for the dopamine and serotonin transporters [1, 4, 18]. It has been further shown that striatal activity is associated with dopamine transporters alone, since serotonin transporters are located in the midbrain [14, 15, 21]. Van Dyck et al. [8] have demonstrated that an equilibrium analysis approximately 18–24 h after injection yields an adequate measure of dopamine transporter density when striatal activity is related to occipital uptake. Therefore our results are in agreement with the above postulation of an increased presynaptic binding capacity of the dopamine transporters. A number of methodological problems must be noted to enable an adequate interpretation of the observations by this study. Because of legal restrictions as to the administration of radioactive agents in the normal population, our control group was investigated at another site than the TS patients. Therefore it is possible that systematic differences between the two groups were produced by differences in technical specifications. This explanation of the differences observed, however, is very unlikely since the same equipment detector system and the same processing devices were used at both sites. Furthermore, strict quality control using the same tolerance ranges in accuracy in three-dimensional activity representation was performed. Second, preparation of the radiopharmaceuticals may have an effect on the measured activity ratios. Therefore the same source for 123I-β-CIT was used for the SPECT studies at both sites of investigation. Radiochemical purity was determined at each site, and the same standards for purity and specific activity were used. Third, our control group differs from the TS group by including women. The differ-
ence in the gender composition of the two groups, however, does not appears to be a major obstacle for comparing ST/OC ratios as gender differences regarding this parameter were not observed in our own control group nor have they been described in the literature [8]. These considerations support the differences observed between the groups in terms of pathology of TS, i. e., that the presynaptic binding capacity is on average increased in this disease. In principle, this finding is in agreement with the results of a postmortem study showing increased binding of [3H]mazindol to the dopamine transporter in three patients [25], with the finding by Wong et al. [29] that elevated dopamine transporter reuptake site capacities using 11C-WIN 35.428 in nine patients, and with the study by Malison et al. [16] who reported increased 123I-β-CIT striatal activity in five TS patients. In contrast to the studies quoted, however, our TS population was heterogeneous regarding dopamine transporter binding capacity. Only 5 of 12 patients had ST/OC ratios exceeding the range of control values. Thus our results are also partly in line with two recent studies – each investigating ten patients suffering from TS – which failed to demonstrate any difference in mean 123I-β-CIT binding in the striatum between TS patients and normal controls [13, 20]. Additionally, Heinz et al. [13] found no relationship between tic severity and striatal 123I-β-CIT binding, and Schindler et al. [20] found no difference in striatal binding in drug-naive patients and patients who were drug free but had received prior neuroleptic treatment. Inconsistent results concerning the 123I-β-CIT binding in TS patients might be explained by the following facts. Comparing the studies with regard to their methodology, it is conspicuous that the two studies reporting no difference in mean 123I-β-CIT binding between TS patients and normal controls used the cerebellum as reference region [13, 20]. In contrast, the study of Malison et al. [16] and our own study used the occipital cortex as reference region. We preferred to calculate the ST/OC ratio because the location of the cerebellum in the posterior fossa often results in increased scatter and attenuation. Furthermore, for methodological reasons all investigators have studied only a relatively small number of patients. TS, however, is now recognized as a complex neuropsychiatric spectrum disorder in which tics are only one of many symptoms. When comparing one study to another it can therefore be speculated that the degree of homogeneity among patients regarding their clinical symptoms – including not only tics but also behavioral disorders – was probably quiet low. In addition, it has been suggested that inconsistent findings may be due to effects of drug exposure [13, 20]. Relating clinical parameters to ST/OC ratios, we found a significant association between binding ratios and the features “self-injurious behavior” and “lack of impulse control.” None of the other clinical features (severity of the disease, tic frequency, attention deficit hyperactivity disorder, OCB, addiction, anxiety, depression, disease duration,
519
and kind of medication) demonstrate an association with normal or increased striatal 123I-β-CIT uptake. These results, however, should be interpreted with caution because our sample size was relatively small. Furthermore, our study included a relatively high number of patients with comorbid self-injurious behavior (67 %) and lack of impulse control (67 %). Therefore it must be assumed that patients with this type of associated behavior were overrepresented in this study. However, previous studies in animals have also suggested involvement of the dopaminergic system in both self-injurious behavior and impulsivity [12, 26, 30]. Thus it can be speculated that the dopamine transporter capacity in TS is affected by additional behavioral disturbances, and that an increase in striatal 123I-β-CIT binding is more likely when “self-injurious behavior” and “lack of impulse control” are associated. To date, no conclusive explanation has been given for changes in the dopaminergic system. It remains unknown whether an increase in transporter capacity is due to an upregulation of the binding sites in consequence of dopamine depletion in the synaptic cleft or to an intrinsic enhance-
ment of the affinity of the transporters. A causative role of dopamine depletion would be supported by the observation of an enhanced binding capacity of the postsynaptic dopamine transporters. This alteration has been established for patients with primary Parkinson’s disease and is considered to be the consequence of compromised dopa synthesis by presynaptic neurons. While an increase in D2 receptor binding has been described by Wolf et al. [28], other groups have reported no differences in [123I]iodo–6methoxybenzaminde or 11C-raclopride striatal binding using SPECT or PET, respectively [9, 17, 27]. These contradictory reports in the literature may reflect the heterogeneity as to dopaminergic involvement in TS patients and are in agreement with the heterogeneity of results in our own patient group. Therefore we postulate that an increase in dopamine transporter capacity is a possible but not a necessary pathophysiological alteration associated with TS. Changes in presynaptic function appear more likely when self-injurious behavior and lack of impulse control are features.
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