An FP-CIT PET comparison of the difference in dopaminergic neuronal loss in subtypes of early Parkinson’s disease

Abstract

Background

Patients with tremor-dominant Parkinson’s disease (PD) have slower disease progression, show less cognitive decline, and have more favorable outcomes than patients with non-tremor PD. However, the pathophysiology of PD tremor remains unclear. Whether there are differences in nigrostriatal dopaminergic dysfunction between the two PD subtypes is unknown.

Purpose

To evaluate the differences in regional dopamine transporter (DAT) density in the brain between different subtypes of early PD using FP-CIT PET/CT.

Material and Methods

We recruited 43 patients with PD (21 tremor-dominant PD [TP] and 22 non-tremor-dominant PD [NTP]) and 18 age-matched healthy controls. All patients with PD underwent FP-CIT PET/CT imaging and evaluated Parkinsonian motor severity by using the Hoehn and Yahr stage and Part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). We also compared tremor and non-tremor symptoms with motor phenotype scores between two subtypes of PD.

Results

All patients with PD demonstrated a significantly decreased FP-CIT uptake in the putamen compared to healthy controls. Differences in putamen FP-CIT uptake versus caudate nucleus FP-CIT uptake in PD showed putamen uptake was significantly more impaired than that in the caudate nucleus. However, there was no significant difference in FP-CIT uptake in the striatum between both PD groups at the same early stage of disease.

Conclusion

We suggest that differential of DAT uptake in the striatum did not allow for a reliable separation of subtypes into tremor-dominant and non-tremor-dominant, especially in the early stages of PD. Therefore, we assumed that many systems besides the nigrostriatal dopaminergic system are involved in the generation of tremors in PD.

Keywords

Parkinson’s disease tremor FP-CIT PET nigrostriatal dopaminergic system

Introduction

To date, the clinical diagnosis of Parkinson’s disease (PD) relies on the presence of cardinal motor features and a favorable response to dopaminergic therapy. However, the diagnosis of PD can be difficult because several neurodegenerative and basal ganglia disorders may present with similar signs and symptoms. Furthermore, it is more difficult to diagnose PD in its early stages because of atypical clinical features at onset and incomplete dopaminergic responsiveness (1). Although the accuracy of a clinical diagnosis of PD is high in specialized movement disorder centers, neurologists incorrectly diagnose PD in approximately 10% of cases and clinicopathological studies have shown that even in that setting, up to 25% of patients are reclassified at follow-up visits (2,3).

Over the past decade, in-vivo imaging of the nigrostriatal dopaminergic system has provided an opportunity to use objective methods to measure the severity and progression of idiopathic PD (4). Dopaminergic dysfunction in patients with PD has been visualized with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) with various tracers. Previous studies have demonstrated a decreased density of dopamine transporter (DAT) in both the caudate nucleus and the putamen using ¹²³I-n-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (FP-CIT), which is a high-affinity cocaine analog that binds specifically to DATs (5). These studies have also shown that reductions in striatal dopamine transporter levels are inversely correlated with severity of motor dysfunction in PD. However, tremors do not necessarily worsen with disease progression and it is generally not correlated with the severity of the dopaminergic deficit in contrast to rigidity and akinesia (6). Resting tremors are considered the most specific among the cardinal PD symptoms and most patients with PD exhibit a resting tremor at some point during their disease (7). The pathophysiology of the PD tremor is still unclear and most studies support the possible involvement of other neurotransmitters such as serotonin, which has also been recently supported by imaging studies (8,9). Furthermore, there is clear evidence that different subtypes of PD show different clinical courses (6,10). Patients with tremor-dominant PD (TP) show a slower progression of the disease, less cognitive decline, and more favorable outcomes than patients with non-tremor-dominant PD (NTP) (10). However, it is also unclear as to whether there are differences in nigrostriatal dopaminergic dysfunction between these two different subtypes. Therefore, we evaluated differences in regional DAT density in the brain between different subtypes of early PD using FP-CIT PET/CT.

Material and Methods

Subjects

The local ethics committee approved this study, each patient and healthy control provided written informed consent (IRB No. OC13RISI0036). All patients were prospectively recruited and the study was conducted between June 2010 and March 2011. We recruited 43 patients with PD (mean age, 66.9 ± 9.15 years) and 18 age-matched healthy controls (mean age, 66.26 ± 10.22 years). Of the 43 patients with PD, 21 had TP (mean age, 64.95 ± 8.95 years) and 22 had NTP (mean age, 67.45 ± 8.58 years). The mean disease duration of all subjects with PD was 23.53 ± 13.91 months and of these, TP and NTP were 19.71 ± 9.01 months and 25.86 ± 18.77 months, respectively (Table 1). The healthy control group did not have any history or symptoms of PD, involuntary movements such as tremor, myoclonus and dyskinesia, or other cognitive dysfunctions according to the dementia-screening questionnaire, and they did not have a history of prior brain surgery or other neurological diseases such as head trauma, epilepsy, or stroke. Neurologists specializing in movement disorders at the Movement Disorder Clinic of Incheon St. Mary’s Hospital examined all patients with PD. A diagnosis of idiopathic PD was made according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnosis Criteria. We evaluated the severity of patients using the Hoehn-Yahr staging (H-Y staging) (11) measure as well as the Unified Parkinson’s disease Rating Scale (UPDRS) Part III. We selected only patients with H-Y staging 1 and 2 for analyzing differences between different subtypes of early stage PD. We also attempted to compare tremor and non-tremor symptoms with motor phenotype scores between TP and NTP. The motor phenotype score was obtained by dividing a patient’s ‘‘tremor score’’ by their ‘‘non-tremor score’’. The tremor score was derived from the sum of items 16 and 20–26 on the UPDRS divided by 8 (the number of items included) and represents the degree of tremor reported in the activities of daily living section of the UPDRS, along with objective tremor at rest and during action, determined on physical examination. The non-tremor score was derived from the sum of items 5, 7, 12–15, 18, 19, and 27–44 on the UPDRS divided by 26 (the number of items included) (12). This measure assesses speech, swallowing, ability to turn in bed, falls, freezing, and walking from the activities of daily living section as well as speech, facial expression, rigidity, bradykinesia, ability to stand, posture, gait, and postural stability determined by the UPDRS motor examination.

Table 1.

Demographic and clinical characteristics.

NTP	TP	Healthy controls	P value
Subjects (n)	22	21	18
Age (years)	67.45 ± 8.58	64.95 ± 8.95	66.26 ± 10.22	0.348
Sex (Female:Male)	14 : 8	16 : 5	13 : 5	0.879
Duration of levodopa therapy (months)	23.82 ± 12.80	17.24 ± 8.50	–	0.059
Duration after initial symptoms (months)	25.86 ± 18.77	19.71 ± 9.01	–	0.478
MMSE score	27.00 ± 1.15	28.42 ± 1.26	29.01 ± 0.98	0.898
Hoehn-Yahr staging	1.64 ± 0.49	1.45 ± 0.65	–	0.225
UPDRS part III	13.73 ± 3.06	14.43 ± 3.25	–	0.981
Tremor score	0.10 ± 0.12	0.59 ± 0.16	–	0.0001
Non-tremor score	0.50 ± 0.12	0.42 ± 0.11	–	0.079
Daily levodopa dosage (mg)	682.20 ± 340.15	376.50 ± 173.76	–	0.003
Daily dopammine agonist dosage (mg)	1.48 ± 1.18	1.71 ± 1.52	–	0.681

Values were expressed mean ± standard deviation, P values were measured by Mann-Whitney U test and Chi-square analysis.

MMSE, Mini-Mental State Examination; NTP, non-tremor-dominant Parkinson’s disease; TP, tremor-dominant Parkinson’s disease.

The evaluation procedure consisted of taking a detailed medical history, physical and neurological examinations, neuropsychological assessments, laboratory tests, and magnetic resonance imaging (MRI) of the brain. Patient with PD did not have a history or symptoms of memory impairment or other cognitive dysfunctions (as measured by the dementia screening questionnaire), nor did they have any cerebrovascular lesions (as measured by neuroimaging). In addition to the aforementioned exclusion criteria, we also excluded patients with secondary causes of Parkinsonism (e.g. Wilson’s disease, neuroleptic drug users, and psychiatric diseases) that would, in judgment of the investigators, interfere with the safe conduct of the study. We also excluded patients that showed orthostatic hypotension, a gaze palsy of eye movement, and a poor response to dopaminergic therapy.

F-18 FP-CIP PET CT

Patients were allowed to continue anti-Parkinsonism medication. However, drugs that may reduce specific to non-specific striatal binding such as d-amphetamine, methylphenidate, benzatropine, buproprion, cocaine, mazindol, and phentermine, were restricted before the exam. Patients were given 149–259 MBq of F-18 FP-CIT (3.7 MBq/kg) intravenously. PET/CT scans were acquired 90 min after the F-18 FP-CIT injection with eyes closed (Discovery STE, GE Healthcare, Milwaukee, WI, USA) (Fig. 1). Data were acquired in three-dimensional mode. CT scanning began at the vertex and progressed to the skull base (30 mAs; 140 kVp; slice, 3.75 mm) and PET imaging followed immediately over the same region with a 15-min duration. CT data were used for attenuation correction and images were reconstructed using the standard ordered subset expectation maximization (OSEM: 2 iterations, 8 subsets) algorithm.

Fig. 1.

FP-CIT PET images in Parkinson’s disease.

Image analysis

An experienced nuclear medicine physician reviewed early and delayed PET/CT images at a workstation (Advantage Workstation version 4.3, GE Healthcare, Milwaukee, WI, USA). A standard set of regions of interest (ROIs) was used to sample the average standardized uptake value (SUVavg) of both the caudate and putamen, and a non-specific reference region in the occipital cortex at the sum images of two or three transverse planes. The putamen was divided into anterior and posterior halves along its longitudinal axis. Ratios of specific to non-specific binding (SOR) were calculated by dividing the striatal count density of DAT by the occipital count density of DAT.

Statistical analysis

All semi-quantitative data are expressed as the mean ± standard deviation. FP-CIT uptake values and continuous variables were compared between patients with PD and the control group using the Mann-Whitney test. Categorical variables were analyzed by using Chi-square analyses. Statistical significance was assumed at the 5% level, two-tailed. Statistical analyses were performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA).

Results

Demographic characteristics are summarized in Table 1. The two PD groups (TP and NTP) did not show any statistically significant differences in regard to age at the time of the PET CT, duration of levodopa therapy, disease duration, H-Y staging, and UPDRS score. Interestingly, there were no significant differences in non-tremor scores between the two groups, but tremor scores were clinically higher in TP than NTP (P = 0.0001). However, daily levodopa dosage was significantly higher in the NTP than the TP (P = 0.003).

The SOR that were measured at 90 min after the FP-CIT injection in both the caudate nucleus and the putamen did not significantly differ between TP and NTP (Fig. 2). However, the SOR in the putamen of the two groups with PD were significantly lower compared to the healthy control group (P < 0.001), especially in the posterior putamen (Fig. 2 and Table 2).

Fig. 2.

SOR of FP-CIT in normal participants and patients affected by NTP and TP. SOR of FP-CIT that were measured at 90 min after the FP-CIT injection in both the caudate nucleus and the putamen did not significantly differ between the patients with NTP and TP. However, the SOR of FP-CIT of the two groups with idiopathic Parkinson disease demonstrated a significantly decreased density compared with that of the healthy control group in the putamen, especially in the posterior putamen. There are no significant differences in the SOR between NTP and TP. The error bars equal 2 SD. *P value between NTP and the normal group and between TP and the normal group was <0.005. AP, anterior putamen; CN, caudate nucleus; FP-CIT, 123I-n-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane; NTP, non-tremor-dominant Parkinson’s disease; PP, posterior putamen; SOR, striatooccipital uptake ratio; TP, tremor-dominant Parkinson's disease.

Table 2.

SOR of FP-CIT PET/CT in patients affected by Parkinson’s disease and healthy subjects.

Location	PD (n = 43) NTP (n = 22)/TP (n = 21)	Control (n = 18)	P value
90 min caudate nucleus	3.71 ± 0.65	4.70 ± 0.76	0.001
90 min caudate nucleus	3.71 ± 0.63/3.70 ± 0.67	4.70 ± 0.76	0.963
90 min anterior putamen	3.19 ± 0.63	5.00 ± 0.77	<0.001
90 min anterior putamen	3.24 ± 0.54/3.14 ± 0.71	5.00 ± 0.77	0.503
90 min posterior putamen	2.20 ± 0.58	5.04 ± 0.77	<0.001
90 min posterior putamen	2.30 ± 0.50/2.11 ± 0.65	5.04 ± 0.77	0.172

PD, idiopathic Parkinson’s disease; NTP, non-tremor-dominant Parkinson’s disease; SOR, striatooccipital uptake ratio; TP, tremor-dominant Parkinson’s disease.

Discussion

In the present study, we confirmed that patients with PD had a significantly lower density in the putamen compared to healthy controls. Compared to healthy controls, patients with PD also showed greater impairment in putamen FP-CIT uptake versus caudate nucleus FP-CIT uptake. These findings converge with previous imaging studies of DAT density (13,14). We analyzed and compared FP-CIT uptake in striatal regions between TP and NTP. However, no difference in FP-CIT uptake was demonstrated between the two groups. Previous FP-CIT SPECT studies have reported that patients with tremor-dominant PD have significantly higher levels of FP-CIT uptake in striatal areas than patients with non-tremor-dominant PD at the same H-Y stage, but this difference has not been fully explained (9,15). Another FP-CIT SPECT study has reported that standardized semi-quantitative analysis of FP-CIT scans did not show significant differences between TP and NTP (10). On the basis of the aforementioned studies and our FP-CIT PET/CT study, we suggest that whether a differential FP-CIT uptake allows for a reliable separation of PD subtypes into tremor-dominant and non-tremor-dominant PD remains controversial.

Our results indicate that tremor in early PD is not closely correlated with nigro-striatal functions. Therefore, we assume that tremor in PD is probably associated with a more complex and heterogeneous pathophysiology compared to other cardinal symptoms. Multiple brain locations and multiple neurotransmitter systems potentially contribute to the manifestation of tremor, and the contribution of dopaminergic, serotoninergic, and cholinergic systems can vary among patients. The dopaminergic role is well-known, having been shown in pathological and imaging studies (9,16,17). One previous neuroimaging study reported that DAT density decrement in TP was pronounced in the caudate nucleus ipsilateral to the clinically affected body side (6). Further, this study showed that patients with tremors had a more widespread and bilateral loss of dopamine nerve terminals in the striatum compared to a group of PD with similar bradykinesia and rigidity scores, but without tremor (6). The role of the caudate nucleus in the onset of tremor has been elucidated only in animal models. Lalley et al. reported tremor induction by intracaudate injections of bretylium, tetrabenazine, and mescaline. Tremor was then suppressed by local injections of catecholamines (18). These results suggest that interference with the local dopamine inhibitory mechanism in the caudate nucleus might lead to the development of tremors (18). However, the evidence of lesser efficacy of dopaminergic therapy on tremor in PD than on other cardinal symptoms emphasizes that other neural systems – apart from the nigrostriatal dopaminergic system – may contribute to generation of tremor in PD (6,15).

The results of the present study showed that the daily dopamine dosage of patient with NTP was higher dose than that of patient with TP. However, these two groups did not differ in disease duration, age, cognitive evaluation, and non-tremor scores. Therefore, we could confirm that motor symptoms of TP show better response of levodopa therapy than those of NTP, even if TP have non-tremor symptoms. These findings were consistent with previous studies suggesting better response to levodopa treatment and prognosis in patients with TP rather than NTP (9,10,19).

The present study had limitations. Although the study was limited by a relatively small number of patients, this may not limit the importance of the observations since the group of patients was relatively homogeneous. Another limitation of our study was related to ROI analysis. To avoid subjective errors in ROI drawing and to obtain more accurate results, we chose the simplest method of applying ROI by one expert physician.

In conclusion, the present FP-CIT PET/CT study show that there is no significant difference in DAT uptake in the striatum between TP versus NTP at the same early stage of the disease. We could show that differential of DAT uptake in striatum did not allow a reliable separation of subtypes into TP and NTP, especially in early stage PD. Therefore, we could assume that systems other than the nigrostriatal dopaminergic system are likely involved in the generation of tremor in PD.

Footnotes

Funding

The research was supported by grant 2012K001490 from the Converging Research Center Program through the Ministry of Education, Science, and Technology.

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