Positron Emission Tomography of Striatal Serotonin Transporters in Parkinson Disease

ORIGINAL CONTRIBUTION Positron Emission Tomography of Striatal Serotonin Transporters in Parkinson Disease

Levente Kerenyi, MD; George A. Ricaurte, MD, PhD; David J. Schretlen, PhD; Una McCann, MD; Jozsef Varga, PhD; William B. Mathews, PhD; Hayden T. Ravert, PhD; Robert F. Dannals, PhD; John Hilton, PhD; Dean F. Wong, MD, PhD; Zsolt Szabo, MD, PhD

Background: Little is known about serotonin neurons cific distribution volumes of [11C](+)McN5652 in the cau- in Parkinson disease (PD). date (PϽ.01) and putamen (PϽ.01), along with the expected reductions in striatal [11C]WIN35428 binding Objective: To study the serotonin system in PD with (PϽ.01). There were no reductions in regional cerebral positron emission tomography, using the serotonin trans- blood flow or the sizes of the regions of interest, miti- porter radioligand [11C](+)McN5652. gating against potential confounding effects of blood flow, brain atrophy, or partial volume effects. Reductions in Design and Patients: We measured the density of the serotonin transporter binding correlated with ratings of serotonin transporter and the density of [11C]WIN35428– disease staging. labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To as- Conclusions: These results suggest that the density of sess the effects of possible differences in blood flow or serotonin transporters, like that of dopamine transport- brain atrophy, we also measured regional cerebral blood ers, is reduced in the striatum of patients with PD and flow and the size of the regions of interest for the cau- that these changes are related to disease stage. date nucleus and putamen.

Results: Patients with PD showed reductions in the spe- Arch Neurol. 2003;60:1223-1229

ARKINSON DISEASE (PD) is high specificity and selectivity for the SERT, characterized by a progres- has been developed.14 The distribution of sive loss of neurons in subcor- [11C](+)McN5652 correlates well with the tical monoaminergic nuclei, known distribution of the SERT in hu- particularly those in the sub- mans,14 and yields a reliable assessment of stantia nigra.1,2 Both in vitro3,4 and in vivo5,6 SERT binding in brains with a docu- P 15,16 studies have yielded extensive evidence of mented loss of 5-HT innervation. reduced dopamine (DA) innervation in the The aim of this study was to assess the brains of patients with PD. In contrast, rela- status of striatal 5-HT innervation in living tively little is presently known about the sta- patients with PD, using [11C](+)McN5652 tus of brain serotonin (5-HT) neurons in and PET. In particular, we sought to: (1) PD.7-9 Further, the clinical significance of evaluate SERT binding in the striatum in PD From the Department of 5-HT changes observed thus far in post- patients; (2) explore the relationship be- Neurology, Medical School 10 Debrecen (Dr Kerenyi); mortem studies is largely unknown. tween changes in the SERT and DAT in pa- Department of Nuclear With modern brain imaging, it is now tients with PD; (3) determine whether al- Medicine, University of possible to selectively image neuron sys- terations in the SERT or DAT in patients Debrecen (Dr Varga), tems of interest in the living human brain. with PD are related to alterations in re- Debrecen, Hungary; the Various investigators have used [123I]␤- gional cerebral blood flow; and (4) deter- Department of Radiology, Johns CIT with single-photon emission com- mine if changes in the SERT and DAT cor- Hopkins Medical Institutions puted tomography (SPECT) to visualize relate with clinical stages of PD. (Drs Ricaurte, Ravert, Dannals, striatal DA innervation and midbrain sero- Hilton, Wong, and Szabo), tonin transporter (SERT) density simulta- Baltimore Md; the Department neously.11-13 For the present studies, METHODS of Psychiatry and Behavioral [123I]beta-CIT was not ideal because it pref- Sciences, School of Medicine STUDY PARTICIPANTS (Dr Schretlen and McCann), erentially labels the DA transporter (DAT) and the Division of Nuclear rather than the SERT in the striatum. Re- A total of 26 subjects participated in the study: Medicine (Dr Mathews), Johns cently, [11C](+)McN5652, a positron emis- 13 adults with idiopathic PD and 13 normal Hopkins University, Baltimore. sion tomography (PET) radioligand with controls (NCs). Patients ranged in age from 54

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 to 75 years (mean±SD, 65.2±7.6 years), had completed 13.8±4.2 After both the [11C](+)McN5652 and [11C]WIN 35428 injec- years of education, and included 6 men and 7 women. Pa- tions, arterial blood samples were drawn manually to obtain tients with PD were recruited from the Johns Hopkins Bay- the input function for compartmental analysis. The input func- view Medical Center Movement Disorder Clinic (Baltimore, Md), tion was corrected for metabolized radioligand activity.24 15 where the diagnosis of idiopathic PD was made based on the After the [ O]H2O injection, arterial blood was drawn from clinical criteria described by Hughes et al.17 In addition, 13 NCs, the radial artery using an automated blood sampler pump and who ranged in age from 38 to 76 years (mean±SD, 63.0±11.5 propelled through a coincidence counting device cross- years), had completed 13.8±2.4 years of education, and in- calibrated with the PET scanner. To determine time activity cluded 7 men and 6 women, participated in the study. curves from ROIs, PET and MRI images were converted to All of the PD patients and NCs were administered the NetCDF/MINC format25 (http://www.bic.mni.mcgill.ca/software Hamilton Rating Scale for Depression18 and the Structured Clini- /minc/minc.html); coregistration was achieved with the Auto- cal Interview for the Diagnostic and Statistical Manual of Men- mated Image Registration algorithm software package.26 Re- tal Disorders, Fourth Edition.19 None of the patients or control gions of interest were drawn on a single slice, which was selected subjects was thought to have major depression, dementia, cur- based on the judgment that it contained the best representa- rent alcohol abuse, or any other Axis I mental disorder. Any tion of that particular brain area. Regions of interest were drawn participant who earned a score of less than 24/30 on the Mini- for the following brain regions: head of caudate, putamen, cer- Mental State Examination20 was excluded. All of the patients ebellum (Figure 1), and thalami (not shown). WIN35428 and underwent neurologic and physical examinations. Disease stag- McN5652 images were coregistered using the same MRI im- ing was assessed with the Hoehn-Yahr Scale (HYS).21 On this age. The same ROIs were used for both tracers, and fitting was basis, 5 patients were rated as being in stage 1, 4 in stage 2, 2 checked visually in each case by codisplay of the PET and MRI in stage 3, and 2 in stage 4. Disease severity, assessed while most images with the ROIs. patients (12 of 13) were taking antiparkinsonian medication, Striatal binding of [11C]WIN35428 was expressed by the was determined using the Unified Parkinson’s Disease Rating ROI/cerebellum tissue activity ratio27 between 55 and 75 min- 11 Scale.22 Finally, each patient completed a self-rating scale of com- utes after injection. [ C](+)McN5652 binding was quantified petence for activities of daily living.23 Twelve of the 13 pa- with the (apparent) total distribution volume that was derived 14 tients with PD were receiving treatment with 1 or more anti- from a 1-compartment, 3-parameter model. The distribution 28 parkinsonian medications at study entry; 1 patient was drug volume of specific binding (DVsp) was calculated as DVsp= naive. Medications included levodopa/carbidopa (n=7), sele- (DVtot - DVcer)/DVcer, where DVcer is the radioligand distribu- giline (n=11), and pramipexol (n=2). None of the patients had tion volume in the cerebellum. Using the PET scans of the 15 taken any medication for at least 12 hours before the PET study. [ O]H2O study, regional cerebral blood flow was calculated from No participants were using medications known to cause per- tissue activity curves derived using the same ROIs as for the sistent alterations in the density of the SERT or DAT. The study radioligand studies. Before fitting these tissue curves, the ar- was approved by the Johns Hopkins University institutional re- terial input function was corrected for bolus delay and disper- 29 view board, and all subjects gave written informed consent to sion. participate. STATISTICAL ANALYSIS IMAGING PROCEDURES The primary hypothesis of the study was that patients with PD To ensure the reproducibility of positioning for the 3 PET stud- would have significant reductions in the DAT and SERT com- ies, a custom-made face mask was fitted to each participant’s pared with age- and sex-matched NCs. A secondary hypoth- head and attached to the head-holder during magnetic reso- esis was that reductions in the DAT and SERT would be posi- nance imaging (MRI) and PET. Magnetic resonance imaging tively correlated with the stage of illness (HYS). was performed to position the subject’s head and delineate the Prior to hypothesis testing, t tests were conducted be- regions of interest (ROIs) using a GE Signa 1.5-T scanner (GE tween the PD and NC groups on the following variables: age; Medical Systems, Milwaukee, Wis).14 years of education; Mini-Mental State Examination scores; and During each PET session, all participants received 3 injec- the mean number of voxels in the various ROIs. To test the pri- tions, 1 with [11C](+)McN5652, 1 with [11C]WIN 35428, and 1 mary hypothesis that striatal DAT and SERT binding are re- with [15O]H O. The average injected dose and specific activity duced in PD, analyses of covariance were conducted, covary- 2 Ͻ was 19 mCi (703 MBq) and 6800 mCi/µmol (251600 MBq/ ing for age. A probability of P .05 was set as the cutoff for µmol) for [11C](+)McN5652, and 19 mCi (703 MBq) and 4700 statistical significance, with a correction for multiple test vari- 30 mCi/µmol (173900 MBq/µmol) for [11C]WIN 35428. The in- ables to control for a type I error. Pearson correlation analy- 15 ses were used to assess relationships between disease severity jected dose for [ O]H2O was 75 mCi (2775 MBq). A GE 4096Plus Whole Body PET Scanner was used for imaging, and 15 simul- and SERT and/or DAT binding. Data are give as mean±SD un- taneous slices, spaced 6.5 mm apart, were acquired. The trans- less otherwise indicated. axial (in-plain) resolution was 5.4 mm (full width at half maximum), with an average axial resolution of 6 mm (full width at RESULTS half maximum) in the center of the field of view. A transmission scan was obtained with a 10-mCi (370-MBq) 68Ge/68Ga pin The PD and NC groups did not differ significantly with source for 10 minutes and was used for attenuation correction respect to age (P=.58), years of education (Mini-Mental of the PET images. First, the WIN35428 tracer was injected. 15 11 State Examination score, 28.1±1.6; P=.57), or sex dis- [ O]H2O was injected after the first study ended. [ C](+) 15 tribution. Figure 1 shows ROIs derived from MRIs to McN5652 was injected 30 minutes after the end of the [ O]H2O coregister with PET imaging. Comparisons revealed that study. Eighteen serial dynamic PET images were acquired after the patients with PD and the NCs did not differ in the the [11C](+)McN5652 injection was given during 95 min- sizes of their respective caudate nuclei (1.19 ±.20 vs utes.14 Seventeen PET scans were obtained during a 75- 1.14±0.19 mL), putamen (2.16 ±.34 vs 2.25±0.27 mL), 11 15 minute injection with [ C]WIN 35428. After the [ O]H2Oin- or cerebellum (10.12±1.84 vs 10.34±1.73 mL) (all P val- jection, 41 serial PET images were acquired in 300 seconds. ues Ͼ.10). Thus, the PD patients did not demonstrate

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 1. Regions of interest (ROIs) superimposed on registered positron emission tomography and magnetic resonance imaging scans used for calculation of tissue time activity curves. The upper images show the ROI of the cerebellum. The lower images show the ROIs of the right and left caudate and right and left putamen.

evidence of atrophic changes in these structures on any the NCs (1.39±0.82) and PD patients (0.69±0.30) in the of the MRI measurements. caudate SERT density was significant (F=7.97; P=.01). Similarly, in the putamen, the distribution volume of spe- [11C](+)McN5652 BINDING cific binding of [11C](+)McN5652 was reduced in PD patients (NC: 1.50±0.58; PD: 0.98±0.31; F=7.52; P=.01), Binding of [11C](+)McN5652 was reduced in the cau- with no significant covariance effect of age (F=1.52; date of subjects with PD (Table 1 and Figure 2). The P=.23) (Table 1). Unlike DAT, SERT binding was not distribution volume of the cerebellum, used to assess non- disproportionately reduced in striatal nuclei contralat- specific binding of [11C](+)McN5652, was not statisti- eral to the more affected side of the body among PD pa- cally different between NCs and PD patients (NC, tients with asymmetric tremor or rigidity (all P values 21.0±7.0; PD, 18.4±3.9; F=1.77; P=.12), and the co- Ͼ.5). There was also a trend for reduced SERT binding variance effect of age on cerebellar distribution volume in the thalami (NC: 1.15±0.69; PD: 0.86±0.35); how- was not significant (F=2.23; P=.15). The hypothesized ever, the difference did not reach the expected level of reduction of the SERT in the striatum of patients with significance (P=.1). PD, as measured by [11C](+)McN5652 binding (distribution volume of specific binding), was compared with [11C]WIN35428 BINDING a P value of .04, adjusted for multiple comparisons and correlations.30 The covariance effect of age was not sig- The binding of [11C]WIN35428 to the DAT was tested nificant (F=0.173; P=.68), but the difference between by the general linear model using diagnosis as a refer-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 CEREBRAL BLOOD FLOW AND LIGAND UPTAKE Serotonin and Dopamine Transporter Binding in the Caudate and Putamen Among Patients With Striatal cerebral blood flow did not differ significantly be- Parkinson Disease (PD) and Normal Controls (NC)* tween NCs and PD patients (43.1±6.9 vs 49.1±7.6 mL/ 100 g per minute, respectively; PϾ.05). Similarly, the Brain Region NC PD F P † group differences in the ligand uptake parameter, K1, were 11 [ C](+)McN5652 not significant in the caudate (PD: 0.29±0.05 mL/mL of Caudate 1.39 ± .82 0.69 ± 0.30 7.97 .01 Putamen 1.50 ± .58 0.98 ± 0.31 7.52 .01 tissue; NC: 0.29±0.06 mL/mL of tissue; P=.78 for main effect; P=.99 for covariance effect of age) and putamen 11 [ C]WIN35 428 (PD: 0.35±0.05 mL/mL of tissue; NC: 0.35±0.07 mL/mL Caudate 3.027 ± 0.578 2.426 ± 0.554 8.7 .007 Putamen 3.483 ± 0.734 2.130 ± 0.611 38.9 Ͻ.001 of tissue; P=.92 for main effect; P=.97 for covariance effect of age). *Data are given as mean ± SD unless otherwise indicated. Data were analyzed by the general linear model, controlling for the covariance effect of age. COMMENT †Based on correction for multiple parameters and parameter correlations, P values less than .04 were considered significant. Our results indicate that patients with PD have reduced ence variable and the caudate-cerebellum ratio or puta- specific distribution volumes of [11C](+)McN5652 in the men-cerebellum ratio as a test variable while control- caudate and putamen, along with the expected reduc- ling for age. Even though the age effect was significant tion in striatal [11C]WIN35428 binding. Further, no re- in both the caudate (F=15.5; P=.001) and the putamen ductions in regional cerebral blood flow or the sizes of (F=19.3; PϽ.001), after controlling for age, PD patients the various ROIs were observed in PD patients, mitigat- showed lower caudate and putamen [11C]WIN35428 ing against potential confounding effects of blood flow, binding than NCs. The putamen-cerebellum DAT bind- brain atrophy, and partial volume averaging. Taken to- ing ratio was reduced by 39% (F=8.7; P=.007), and the gether, these findings suggest that the density of SERTs, caudate-cerebellum DAT binding ratio was reduced by similar to the density of DATs, is reduced in the stria- 20% (F=38.9; PϽ.001) in PD patients compared with tum of patients with PD, presumably reflecting the loss NCs. Both differences are significant. of serotonergic and dopaminergic innervation, respec- Of the 13 patients with PD, 10 had asymmetric tively. tremor or rigidity (6, rightϾleft; 4, leftϾright). When the Patients with PD showed the expected decrease in ratios of DAT binding were compared for these sub- DAT binding in the striatum. These results are in agree- groups, patients showed a 34% greater reduction in DAT ment with other studies wherein DAT binding decreases binding in the putamen region contralateral to the most in PD have been found to range from 20% to 50% in the affected side of the body, and 6% greater reduction in DAT caudate and from 40% to 70% in the putamen.31-33 Nota- binding in the caudate region contralateral to the most bly, patients with asymmetric tremor or rigidity showed affected side of the body. This asymmetry in DAT bind- a 34% greater decrease in DAT binding in the putamen ing was significant only for the putamen (P=.006). region contralateral to the most clinically affected side of the body, which is also similar to earlier reports.31 Also con- CORRELATION BETWEEN [11C](+)McN5652 sistent with earlier reports,33-35 we found that reductions AND [11C]WIN35428 BINDING in striatal DAT binding correlated with more advanced disease, as measured by the HYS. The present study extends The hypothesis that reductions in DAT and SERT bind- these findings by providing preliminary evidence that re- ing would correlate with a more advanced stage of ill- ductions in striatal SERT binding also correlate with dis- ness was tested by the Spearman correlation of the bind- ease stage. Given the small number of subjects included ing of these ligands in the putamen (part of the striatum in the analysis (n=13), additional studies will be neces- that is more affected in PD than the caudate nucleus) sary to reach definitive conclusions in this regard. with the HYS. In the 13 PD patients, [11C](+)McN5652 A potential drawback of the neuroimaging meth- demonstrated a negative correlation with HYS (r=−0.57; ods we employed was the use of [11C](+)McN5652, a PET P=.04) and a positive correlation with [11C]WIN35428 radioligand that demonstrates considerable nonspecific binding (r =0.57; P =.04). The correlation between binding even in the striatum. Nonspecific binding could [11C](+)McNM5652 binding and [11C]WIN35428 bind- minimize the assessed contrast between the 2 groups of ing was even more significant when NCs and PD subjects and result in an underestimation of differences. patients were combined (r=0.58; P=.002) (Figure 3). The effect of nonspecific binding was minimized, using As expected, the correlation of [11C]WIN35428 binding the cerebellum as a reference region. Normalization in- with HYS was negative (r=−0.62) (P=.02). No correla- cluded both subtraction of and division by the cerebel- tion was found between the binding parameters of both lar distribution volume of striatal total distribution vol- radioligands with the Unified Parkinson’s Disease Rating ume values, attempting to account for effects of both Scale and activities of daily living (all P values Ͼ.05), parameter bias and variance. Although minimal but mea- although the correlations between the clinical scores on surable specific binding in the cerebellum does exist,36 HYS, the Unified Parkinson’s Disease Rating Scale, and using the cerebellum to correct for nonspecific binding activities of daily living were all significant (r=0.84-0.92; appeared to be justified since the difference of cerebel- PϽ.001). lar distribution volume between patients and NCs was

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MCN-NC MCN-PD

Figure 2. Radioligand binding to the serotonin transporter and dopamine transporter in a normal control (NC) subject and in a patient with Parkinson disease (PD). Dopamine transporter binding was imaged 55 to 75 minutes after injection of [11C]WIN35428, and the image was normalized to a minimum of 0 and a maximum activity concentration of 150 nCi/mL per millicurie (injected dose). Serotonin transporter binding was imaged 55 to 95 minutes after injection of [11C]McN(+)5652, and the image was normalized to a minimum of 0 and a maximum activity concentration of 100 nCi/mL per millicurie (injected dose).

40,41 not significant. The cerebellar K1 was 14% lower in the mans is conflicting regarding this issue. While it can- PD than in the NC group; if this effect results in a bias, not be stated unequivocally that previous chronic medi- the actual radioligand binding in PD subjects would be cation use did not alter DAT or SERT binding, significant 14% lower than calculated, and it could falsely blunt but correlations between disease staging and transporter bind- not augment the difference between the 2 groups. ing suggest that potential medication-related effects on The potential role of antiparkinsonian medications transporter binding were not robust. deserves comment. Although subjects had not taken their Another potential methodologic issue related to antiparkinsonian medications for at least 12 hours at the medication use is that at the time PD patients under- time of their PET studies, their chronic use prior to these went clinical evaluation to assess the severity of their dis- studies could have potentially influenced DAT and/or ease, they were using antiparkinsonian medications. This SERT binding characteristics. Importantly, preclinical could potentially have confounded measures relating to studies do not support the view that these medications severity of illness. However, despite the use of medica- lead to alterations in monoamine transporter binding or tions at the time of clinical assessment, significant cor- affinity.37-39 The limited available data collected in hu- relations between striatal [11C]WIN35428 and [11C](+)

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 terial support (Drs Kerenyi, Mathews, Ravert, Dannals, 2.5 Wong, and Szabo); study supervision (Drs McCann and Szabo). 2.0 This research was supported by US Public Health Ser- vice awards AG 14400 (Dr Szabo), DA 05938 (Dr Ricau- 1.5 rte), DA 10217 (Dr Ricaurte), DA 09482 (Dr Wong), and NS38927 (Dr Wong). 1.0 Corresponding author: Zsolt Szabo, MD, PhD, Depart- ment of Radiology, Johns Hopkins Medical Institutions, JHOC 0.5 3233, 601 N Caroline St, Baltimore, MD 21287 (e-mail:

WIN: A65 Putamen/A65 Cerebellum r = 0.58 (All); r = 0.75 (PD Only) [email protected]).

0.0 1.0 2.0 3.0 4.0 5.0 REFERENCES McN: DVSP Putamen

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