Journal of the Neurological Sciences 339 (2014) 207–209
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Comparison of dopamine transporter decline in a patient with Parkinson's disease and normal aging effect Kenji Ishibashi ⁎, Keiichi Oda, Kiichi Ishiwata, Kenji Ishii Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022, Japan
a r t i c l e
i n f o
Article history: Received 22 November 2013 Received in revised form 7 January 2014 Accepted 12 January 2014 Available online 15 January 2014 Keywords: Parkinson's disease Dopamine transporter Positron emission tomography Striatum Aging 11 C-CFT
a b s t r a c t We report serial dopamine transporter (DAT) positron emission tomography (PET) scanning in a patient with Parkinson's disease (PD). Six months after motor symptom onset, the patient was diagnosed with PD, Hoehn– Yahr stage 1 at age 71, and underwent DAT PET scanning at ages 71, 72, 74, and 75. Volumes-of-interest were placed on the ventral striatum (vST), pre-commissural dorsal caudate (preDCA), post-commissural caudate (postCA), pre-commissural dorsal putamen (preDPU), and post-commissural putamen (postPU); the results were compared to the age-related regression line created by using the data of 16 healthy subjects. For the patient, DAT availability in the vST, preDCA, postCA, preDPU, and postPU at the first scanning was 5.5%, 26.2%, 29.9%, 34.5%, and 60.2% lower, respectively, compared to the age-related regression line. The rates of DAT decline in the vST, preDCA, postCA, preDPU, and postPU were 5.3%, 5.4%, 8.5%, 6.2%, and 7.8% per year, respectively. The postPU is well known to be an initial region of DAT decline and be severely affected throughout the illness. If the decline follows an exponential pattern, in this case, DAT decline in the postPU is speculated to start about 10 years before the motor symptom onset. © 2014 Elsevier B.V. All rights reserved.
1. Introduction
2. Materials and methods
Parkinson's disease (PD) is a neurodegenerative disorder caused by nigrostriatal dopaminergic dysfunction. Postmortem data shows that motor signs appeared when 30–50% of the substantia nigra (SN) dopamine neurons degenerated or 50–80% of the striatal dopamine terminals were lost [1–3]. A recent longitudinal positron emission tomography (PET) study showed that the decline of dopamine transporter (DAT) availability in the more affected putamen at the time of motor symptom onset was 62.7% lower as compared to healthy subjects, and indicated that the progression of longitudinal DAT decline followed an exponential trajectory [4]. Moreover, DAT availability is well known to decrease linearly in an age-related manner, and the rates of decline are 6.1% and 5.5% per decade in the caudate and putamen, respectively [5]. The aim of this study was to extend current knowledge on the progression of DAT decline in a patient with PD, focusing on regional differences in comparison with normal aging. In this study, a patient with early PD underwent DAT PET scanning with carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl)-tropane ( 11 C-CFT) four times in four years after the time of diagnosis, and the data were compared to normal age-related DAT decline in each of the striatal subregions.
2.1. Research participants All procedures were approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology. After a detailed explanation of the study, each participant provided written informed consent. The sample was composed of a female patient with idiopathic PD and 16 healthy subjects (15 men and three women, ages 21 to 74 years). 2.2. A patient with Parkinson's disease Six months after developing right leg tremor, the patient was diagnosed with PD at age 71, and underwent 11C-CFT PET scanning at ages 71, 72, 74, and 75. On initial examination at age 71, she had resting tremor and mild rigidity of her right arm and leg (Hoehn–Yahr stage 1) and normal cognitive function (Mini Mental State Examination score: 30). Levodopa was administered and effective, but without levodopa a mild postural instability developed (Unified Parkinson's Disease Rating Scale motor section score: 11) at age 74. The parkinsonian symptoms were not changed between the third and fourth PET scanning. 2.3. PET scanning
⁎ Corresponding author at: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan. Tel.: +81 3 3964 3241; fax: +81 3 3964 1148. E-mail address: [email protected] (K. Ishibashi). 0022-510X/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2014.01.015
11 C-CFT was synthesized as described in a previous study [6]. PET scanning was performed on a SET-2400W scanner (Shimadzu, Kyoto, Japan) in three-dimensional mode at the Tokyo Metropolitan
208
K. Ishibashi et al. / Journal of the Neurological Sciences 339 (2014) 207–209
Institute of Gerontology. Images with 50 slices were obtained with a 2.054 × 2.054 × 3.125-mm 3 voxel size and a 128 × 128 matrix size. The transmission data was acquired by using a rotating 68Ga/68Ge rod source for measured attenuation correction. Static emission data were acquired from 75 to 90 min after an intravenous bolus infection of 11 C-CFT. The injection doses were 320 ± 41 MBq, and the specific activities were 39 ± 30 MBq/nmol at the time of injection (mean ± standard deviation). 2.4. Magnetic resonance image (MRI) acquisition and volumes-of-interest (VOIs) MRI scanning was performed on a 1.5-Tesla Signa EXCITE HD scanner (GE, Milwaukee, WI) in the three-dimensional mode (3DSPGR; repetition time = 9.2 ms, echo time = 2.0 ms, matrix size = 256 × 256 × 124, voxel size = 0.94 × 0.94 × 1.3 mm), and processed using the FMRIB Software Library (FSL; Oxford University, Oxford). VOIs included the striatal subregions as target regions and the cerebellum as a reference region. A whole-striatum VOI was created by combining the caudate, putamen, and nucleus accumbens VOIs, anatomically defined in native space using FSL FIRST. The whole-striatum was divided into five anatomical VOIs (Fig. 1A): the ventral striatum (vST), pre-commissural dorsal caudate (preDCA), post-commissural caudate (postCA), pre-commissural dorsal putamen (preDPU), and post-commissural putamen (postPU), as reported previously [7]. A cerebellum VOI was created by transforming a bilateral VOI, drawn manually on the left and right cerebellar hemispheres in MNI152 space, to native space. 2.5. PET image processing The static PET images were co-registered to the corresponding structural MRI, using FSL FLIRT. The VOIs placed on the MRI were moved onto the PET images, and activity data within the anatomically defined VOIs (see above) were extracted from co-registered PET images. To estimate DAT availability in each target region, the non-displaceable binding potential (BPEq) of 11C-CFT was calculated by the following formula: BPEq = [(activity in the target region) − (activity in the
cerebellum)] / [(activity in the cerebellum)]. We have previously validated the use of BPEq [5]. 3. Results For healthy subjects, BPEq and age were negatively correlated in the vST (r = −0.559, p = 0.024), preDCA (r =−0.785, p b 0.001), postCA (r =−0.804, p b 0.001), preDPU (r =−0.667, p = 0.005), and postPU (r =−0.782, p b 0.001) (Fig. 1). For the patient, the rates of DAT decline in the vST, preDCA, postCA, preDPU, and postPU were 5.3%, 5.4%, 8.5%, 6.2%, and 7.8% per year, respectively. At the first scanning, compared to the age-related regression line, the largest reduction of BPEq was found in the postPU (60.2%) followed by the preDPU (34.5%), postCA (29.9%), and preDCA (26.2%). BPEq in the vST was relatively preserved (Table 1). 4. Discussion We showed that the postPU had the lowest BPEq (60.2% reduced) and vST had a relatively preserved BPEq (5.5% reduced) in the patient with PD at six months after motor symptom onset as compared to healthy subjects. The postPU is anatomically equivalent to the dorsal posterior part of the putamen, which is the initial region of DAT decline and is most severely affected throughout the illness [2,8]. Our finding in the postPU was consistent with these previous observations and a recent PET study with a DAT ligand 11C-d-threo-methylphenidate [4]. The vST, which encompasses the nucleus accumbens and the most ventral parts of the caudate and putamen [7,9] and regulates some behavioral symptoms [10], is strongly innervated by dopaminergic fibers from the midbrain ventral tegmental area, where patients with PD show a less pronounced loss of dopaminergic neurons as compared to the contiguous SN pars compacta [11,12]. The rate of dopaminergic dysfunction in the vST at motor symptom onset has not been assessed previously, although a few PET studies with 18F-dopa indicated that the vST was relatively less affected in early PD [13,14]. Our preliminary observation that DAT availability in the vST could be preserved at the time of motor symptom onset might be important to understand behavioral symptoms in patients with PD.
Fig. 1. Relationship between longitudinal dopamine transporter decline in a patient with Parkinson's disease and healthy subjects. (A) An example of volumes-of-interest (VOIs) placed on the ventral striatum (white), pre-commissural dorsal caudate (black), pre-commissural dorsal putamen (red), and post-commissural putamen (blue) within the right hemisphere of axial and coronal sections is shown in a representative PET image superimposed on the corresponding magnetic resonance image. Post-commissural caudate VOI is not shown. (B–F) Scatter plots between age and BPEq values in each of the five regions. Solid lines represent the regression lines for 16 healthy subjects. Open and solid circles are for healthy subjects and the patient with Parkinson's disease (PD), respectively. A dotted red line (F) represents the exponential curve extrapolated from four successive BPEq values in the patient with PD. BPEq: nondisplaceable binding potential representing dopamine transporter availability.
K. Ishibashi et al. / Journal of the Neurological Sciences 339 (2014) 207–209
209
Table 1 Comparison of BPEq decline between a patient with Parkinson's disease and healthy subjects.
Ventral striatum Pre-commissural dorsal caudate Post-commissural caudate Pre-commissural dorsal putamen Post-commissural putamen
Healthy subjects (n = 16)
Patient with Parkinson's disease
BPEq decline (% per year)
BPEq decline from first to fourth PET scan (% per year)
Difference from age-related regression line at first PET scan (%)
0.46 0.69
5.3 5.4
5.5 26.2
0.96 0.51
8.5 6.2
29.9 34.5
0.64
7.8
60.2
BPEq: Non-displaceable binding potential representing dopamine transporter availability, PET: Positron emission tomography.
Our regional analyses suggested that there could be ventral–dorsal and anterior–posterior gradients of DAT decline in patients with PD, and the rate of DAT decline is faster in the dorsal and posterior parts than in the ventral and anterior parts at the time of motor symptom onset. Dopamine neuronal loss in the SN and DAT loss in the striatum is reported to follow an exponential curve by postmortem and PET studies [2,4,15]. One of the limitations of the present study is that this is a case report of a patient with PD and the sample size is not large. PD is a heterogeneous disorder with multiple factors contributing to disease initiation and progression [15,16], and one cannot expect another patient with PD to follow a similar clinical course presented here. However, at least for early PD patients with only motor symptom and without cognitive impairment, presuming that the DAT decline proceeds in an exponential manner in the postPU [2,4,15], Fig. 1F might provide preliminary evidence that DAT decline in the postPU starts about 10 years before motor symptom onset. Disclosure None of the authors has any conflict of interest to disclose. Acknowledgments The authors thank Mr. Keiichi Kawasaki and Ms. Hiroko Tsukinari for their technical assistance and useful discussions. References [1] Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol Jun 2010;67(6):715–25. [2] Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain Oct 1991;114(Pt 5):2283–301.
[3] Marsden CD. Parkinson's disease. Lancet Apr 21 1990;335(8695):948–52. [4] Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, McKenzie J, et al. Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease. Brain Nov 2011;134(Pt 11):3290–8. [5] Ishibashi K, Ishii K, Oda K, Kawasaki K, Mizusawa H, Ishiwata K. Regional analysis of age-related decline in dopamine transporters and dopamine D2-like receptors in human striatum. Synapse Apr 2009;63(4):282–90. [6] Kawamura K, Oda K, Ishiwata K. Age-related changes of the [11C]CFT binding to the striatal dopamine transporters in the Fischer 344 rats: a PET study. Ann Nucl Med May 2003;17(3):249–53. [7] Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab Mar 2003;23(3):285–300. [8] Ishibashi K, Saito Y, Murayama S, Kanemaru K, Oda K, Ishiwata K, et al. Validation of cardiac 123I-MIBG scintigraphy in patients with Parkinson's disease who were diagnosed with dopamine PET. Eur J Nucl Med Mol Imaging Jan 2010;37(1):3–11. [9] Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab Sep 2001;21(9):1034–57. [10] Basar K, Sesia T, Groenewegen H, Steinbusch HW, Visser-Vandewalle V, Temel Y. Nucleus accumbens and impulsivity. Prog Neurobiol Dec 2010;92(4):533–57. [11] Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain Aug 1999;122(Pt 8):1437–48. [12] Maingay M, Romero-Ramos M, Carta M, Kirik D. Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression. Neurobiol Dis Sep 2006;23(3):522–32. [13] Bruck A, Aalto S, Nurmi E, Vahlberg T, Bergman J, Rinne JO. Striatal subregional 6[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study. Mov Disord Jul 2006;21(7):958–63. [14] Pavese N, Rivero-Bosch M, Lewis SJ, Whone AL, Brooks DJ. Progression of monoaminergic dysfunction in Parkinson's disease: a longitudinal 18F-dopa PET study. Neuroimage Jun 1 2011;56(3):1463–8. [15] Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, Lee CS, et al. Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study. Brain Nov 2009;132(Pt 11):2970–9. [16] Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry Mar 2005;76(3):343–8.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Comparison of dopamine transporter decline in a patient with Parkinson's disease and normal aging effect Kenji Ishibashi ⁎, Keiichi Oda, Kiichi Ishiwata, Kenji Ishii Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022, Japan
a r t i c l e
i n f o
Article history: Received 22 November 2013 Received in revised form 7 January 2014 Accepted 12 January 2014 Available online 15 January 2014 Keywords: Parkinson's disease Dopamine transporter Positron emission tomography Striatum Aging 11 C-CFT
a b s t r a c t We report serial dopamine transporter (DAT) positron emission tomography (PET) scanning in a patient with Parkinson's disease (PD). Six months after motor symptom onset, the patient was diagnosed with PD, Hoehn– Yahr stage 1 at age 71, and underwent DAT PET scanning at ages 71, 72, 74, and 75. Volumes-of-interest were placed on the ventral striatum (vST), pre-commissural dorsal caudate (preDCA), post-commissural caudate (postCA), pre-commissural dorsal putamen (preDPU), and post-commissural putamen (postPU); the results were compared to the age-related regression line created by using the data of 16 healthy subjects. For the patient, DAT availability in the vST, preDCA, postCA, preDPU, and postPU at the first scanning was 5.5%, 26.2%, 29.9%, 34.5%, and 60.2% lower, respectively, compared to the age-related regression line. The rates of DAT decline in the vST, preDCA, postCA, preDPU, and postPU were 5.3%, 5.4%, 8.5%, 6.2%, and 7.8% per year, respectively. The postPU is well known to be an initial region of DAT decline and be severely affected throughout the illness. If the decline follows an exponential pattern, in this case, DAT decline in the postPU is speculated to start about 10 years before the motor symptom onset. © 2014 Elsevier B.V. All rights reserved.
1. Introduction
2. Materials and methods
Parkinson's disease (PD) is a neurodegenerative disorder caused by nigrostriatal dopaminergic dysfunction. Postmortem data shows that motor signs appeared when 30–50% of the substantia nigra (SN) dopamine neurons degenerated or 50–80% of the striatal dopamine terminals were lost [1–3]. A recent longitudinal positron emission tomography (PET) study showed that the decline of dopamine transporter (DAT) availability in the more affected putamen at the time of motor symptom onset was 62.7% lower as compared to healthy subjects, and indicated that the progression of longitudinal DAT decline followed an exponential trajectory [4]. Moreover, DAT availability is well known to decrease linearly in an age-related manner, and the rates of decline are 6.1% and 5.5% per decade in the caudate and putamen, respectively [5]. The aim of this study was to extend current knowledge on the progression of DAT decline in a patient with PD, focusing on regional differences in comparison with normal aging. In this study, a patient with early PD underwent DAT PET scanning with carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl)-tropane ( 11 C-CFT) four times in four years after the time of diagnosis, and the data were compared to normal age-related DAT decline in each of the striatal subregions.
2.1. Research participants All procedures were approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology. After a detailed explanation of the study, each participant provided written informed consent. The sample was composed of a female patient with idiopathic PD and 16 healthy subjects (15 men and three women, ages 21 to 74 years). 2.2. A patient with Parkinson's disease Six months after developing right leg tremor, the patient was diagnosed with PD at age 71, and underwent 11C-CFT PET scanning at ages 71, 72, 74, and 75. On initial examination at age 71, she had resting tremor and mild rigidity of her right arm and leg (Hoehn–Yahr stage 1) and normal cognitive function (Mini Mental State Examination score: 30). Levodopa was administered and effective, but without levodopa a mild postural instability developed (Unified Parkinson's Disease Rating Scale motor section score: 11) at age 74. The parkinsonian symptoms were not changed between the third and fourth PET scanning. 2.3. PET scanning
⁎ Corresponding author at: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan. Tel.: +81 3 3964 3241; fax: +81 3 3964 1148. E-mail address: [email protected] (K. Ishibashi). 0022-510X/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2014.01.015
11 C-CFT was synthesized as described in a previous study [6]. PET scanning was performed on a SET-2400W scanner (Shimadzu, Kyoto, Japan) in three-dimensional mode at the Tokyo Metropolitan
208
K. Ishibashi et al. / Journal of the Neurological Sciences 339 (2014) 207–209
Institute of Gerontology. Images with 50 slices were obtained with a 2.054 × 2.054 × 3.125-mm 3 voxel size and a 128 × 128 matrix size. The transmission data was acquired by using a rotating 68Ga/68Ge rod source for measured attenuation correction. Static emission data were acquired from 75 to 90 min after an intravenous bolus infection of 11 C-CFT. The injection doses were 320 ± 41 MBq, and the specific activities were 39 ± 30 MBq/nmol at the time of injection (mean ± standard deviation). 2.4. Magnetic resonance image (MRI) acquisition and volumes-of-interest (VOIs) MRI scanning was performed on a 1.5-Tesla Signa EXCITE HD scanner (GE, Milwaukee, WI) in the three-dimensional mode (3DSPGR; repetition time = 9.2 ms, echo time = 2.0 ms, matrix size = 256 × 256 × 124, voxel size = 0.94 × 0.94 × 1.3 mm), and processed using the FMRIB Software Library (FSL; Oxford University, Oxford). VOIs included the striatal subregions as target regions and the cerebellum as a reference region. A whole-striatum VOI was created by combining the caudate, putamen, and nucleus accumbens VOIs, anatomically defined in native space using FSL FIRST. The whole-striatum was divided into five anatomical VOIs (Fig. 1A): the ventral striatum (vST), pre-commissural dorsal caudate (preDCA), post-commissural caudate (postCA), pre-commissural dorsal putamen (preDPU), and post-commissural putamen (postPU), as reported previously [7]. A cerebellum VOI was created by transforming a bilateral VOI, drawn manually on the left and right cerebellar hemispheres in MNI152 space, to native space. 2.5. PET image processing The static PET images were co-registered to the corresponding structural MRI, using FSL FLIRT. The VOIs placed on the MRI were moved onto the PET images, and activity data within the anatomically defined VOIs (see above) were extracted from co-registered PET images. To estimate DAT availability in each target region, the non-displaceable binding potential (BPEq) of 11C-CFT was calculated by the following formula: BPEq = [(activity in the target region) − (activity in the
cerebellum)] / [(activity in the cerebellum)]. We have previously validated the use of BPEq [5]. 3. Results For healthy subjects, BPEq and age were negatively correlated in the vST (r = −0.559, p = 0.024), preDCA (r =−0.785, p b 0.001), postCA (r =−0.804, p b 0.001), preDPU (r =−0.667, p = 0.005), and postPU (r =−0.782, p b 0.001) (Fig. 1). For the patient, the rates of DAT decline in the vST, preDCA, postCA, preDPU, and postPU were 5.3%, 5.4%, 8.5%, 6.2%, and 7.8% per year, respectively. At the first scanning, compared to the age-related regression line, the largest reduction of BPEq was found in the postPU (60.2%) followed by the preDPU (34.5%), postCA (29.9%), and preDCA (26.2%). BPEq in the vST was relatively preserved (Table 1). 4. Discussion We showed that the postPU had the lowest BPEq (60.2% reduced) and vST had a relatively preserved BPEq (5.5% reduced) in the patient with PD at six months after motor symptom onset as compared to healthy subjects. The postPU is anatomically equivalent to the dorsal posterior part of the putamen, which is the initial region of DAT decline and is most severely affected throughout the illness [2,8]. Our finding in the postPU was consistent with these previous observations and a recent PET study with a DAT ligand 11C-d-threo-methylphenidate [4]. The vST, which encompasses the nucleus accumbens and the most ventral parts of the caudate and putamen [7,9] and regulates some behavioral symptoms [10], is strongly innervated by dopaminergic fibers from the midbrain ventral tegmental area, where patients with PD show a less pronounced loss of dopaminergic neurons as compared to the contiguous SN pars compacta [11,12]. The rate of dopaminergic dysfunction in the vST at motor symptom onset has not been assessed previously, although a few PET studies with 18F-dopa indicated that the vST was relatively less affected in early PD [13,14]. Our preliminary observation that DAT availability in the vST could be preserved at the time of motor symptom onset might be important to understand behavioral symptoms in patients with PD.
Fig. 1. Relationship between longitudinal dopamine transporter decline in a patient with Parkinson's disease and healthy subjects. (A) An example of volumes-of-interest (VOIs) placed on the ventral striatum (white), pre-commissural dorsal caudate (black), pre-commissural dorsal putamen (red), and post-commissural putamen (blue) within the right hemisphere of axial and coronal sections is shown in a representative PET image superimposed on the corresponding magnetic resonance image. Post-commissural caudate VOI is not shown. (B–F) Scatter plots between age and BPEq values in each of the five regions. Solid lines represent the regression lines for 16 healthy subjects. Open and solid circles are for healthy subjects and the patient with Parkinson's disease (PD), respectively. A dotted red line (F) represents the exponential curve extrapolated from four successive BPEq values in the patient with PD. BPEq: nondisplaceable binding potential representing dopamine transporter availability.
K. Ishibashi et al. / Journal of the Neurological Sciences 339 (2014) 207–209
209
Table 1 Comparison of BPEq decline between a patient with Parkinson's disease and healthy subjects.
Ventral striatum Pre-commissural dorsal caudate Post-commissural caudate Pre-commissural dorsal putamen Post-commissural putamen
Healthy subjects (n = 16)
Patient with Parkinson's disease
BPEq decline (% per year)
BPEq decline from first to fourth PET scan (% per year)
Difference from age-related regression line at first PET scan (%)
0.46 0.69
5.3 5.4
5.5 26.2
0.96 0.51
8.5 6.2
29.9 34.5
0.64
7.8
60.2
BPEq: Non-displaceable binding potential representing dopamine transporter availability, PET: Positron emission tomography.
Our regional analyses suggested that there could be ventral–dorsal and anterior–posterior gradients of DAT decline in patients with PD, and the rate of DAT decline is faster in the dorsal and posterior parts than in the ventral and anterior parts at the time of motor symptom onset. Dopamine neuronal loss in the SN and DAT loss in the striatum is reported to follow an exponential curve by postmortem and PET studies [2,4,15]. One of the limitations of the present study is that this is a case report of a patient with PD and the sample size is not large. PD is a heterogeneous disorder with multiple factors contributing to disease initiation and progression [15,16], and one cannot expect another patient with PD to follow a similar clinical course presented here. However, at least for early PD patients with only motor symptom and without cognitive impairment, presuming that the DAT decline proceeds in an exponential manner in the postPU [2,4,15], Fig. 1F might provide preliminary evidence that DAT decline in the postPU starts about 10 years before motor symptom onset. Disclosure None of the authors has any conflict of interest to disclose. Acknowledgments The authors thank Mr. Keiichi Kawasaki and Ms. Hiroko Tsukinari for their technical assistance and useful discussions. References [1] Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol Jun 2010;67(6):715–25. [2] Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain Oct 1991;114(Pt 5):2283–301.
[3] Marsden CD. Parkinson's disease. Lancet Apr 21 1990;335(8695):948–52. [4] Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, McKenzie J, et al. Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease. Brain Nov 2011;134(Pt 11):3290–8. [5] Ishibashi K, Ishii K, Oda K, Kawasaki K, Mizusawa H, Ishiwata K. Regional analysis of age-related decline in dopamine transporters and dopamine D2-like receptors in human striatum. Synapse Apr 2009;63(4):282–90. [6] Kawamura K, Oda K, Ishiwata K. Age-related changes of the [11C]CFT binding to the striatal dopamine transporters in the Fischer 344 rats: a PET study. Ann Nucl Med May 2003;17(3):249–53. [7] Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab Mar 2003;23(3):285–300. [8] Ishibashi K, Saito Y, Murayama S, Kanemaru K, Oda K, Ishiwata K, et al. Validation of cardiac 123I-MIBG scintigraphy in patients with Parkinson's disease who were diagnosed with dopamine PET. Eur J Nucl Med Mol Imaging Jan 2010;37(1):3–11. [9] Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab Sep 2001;21(9):1034–57. [10] Basar K, Sesia T, Groenewegen H, Steinbusch HW, Visser-Vandewalle V, Temel Y. Nucleus accumbens and impulsivity. Prog Neurobiol Dec 2010;92(4):533–57. [11] Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain Aug 1999;122(Pt 8):1437–48. [12] Maingay M, Romero-Ramos M, Carta M, Kirik D. Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression. Neurobiol Dis Sep 2006;23(3):522–32. [13] Bruck A, Aalto S, Nurmi E, Vahlberg T, Bergman J, Rinne JO. Striatal subregional 6[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study. Mov Disord Jul 2006;21(7):958–63. [14] Pavese N, Rivero-Bosch M, Lewis SJ, Whone AL, Brooks DJ. Progression of monoaminergic dysfunction in Parkinson's disease: a longitudinal 18F-dopa PET study. Neuroimage Jun 1 2011;56(3):1463–8. [15] Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, Lee CS, et al. Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study. Brain Nov 2009;132(Pt 11):2970–9. [16] Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry Mar 2005;76(3):343–8.
