In recent years, a decrease in striatal dopamine transporter (DAT) uptake associated with age has been reported to be related to impairment because of Parkinson’s disease (PD) and the other parkinsonian symptoms 1. PD is expected to increase as the society ages, and this is considered a serious problem for the future. When the principal motor symptoms appear in early PD, uptake studies also show a decreased striatal DAT uptake and a reduction in the semiquantitative marker specific binding ratio (SBR) 2. DAT binding shows changes concordant with the loss of the nigrostriatal dopamine nerve terminals when less than 50% of nigral neurons have been lost 3. In patients with PD, autopsy shows a lack of tyrosine hydroxylase in cardiac epithelial cells 4 and iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy shows disturbances in the sympathetic nervous system. These have been shown to be useful in the early diagnosis of the disease in studies carried out in Japan and elsewhere 5,6. Supplementary methods for diagnosing PD using nuclear medicine, such as 123I-MIBG scintigraphy, iodine-123-ioflupane (123I-ioflupane) scintigraphy, and the combination of both methods, were found to increase the diagnostic ability of early PD in 18 patients suspected to have the disease 7. However, the significance of adding 123I-MIBG scintigraphy when 123I-ioflupane scintigraphy does not show decreased uptake has not been studied to date. We hypothesized that the diagnostic yield would improve with the combined use of both 123I-MIBG and 123I-ioflupane scintigraphy, and that diagnostic ability would improve even when a decrease in 123I-ioflupane uptake was not observed. The purpose of this study was to verify the utility of the combined use of 123I-MIBG and 123I-ioflupane scintigraphy in suspected cases of new-onset PD.
Patients and methods
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of St Marianna University School of Medicine (approval no. 2974). All patients enrolled provided written, informed consent for participation in this study.
Selection of participants
A single-facility, retrospective case–control study was carried out. Using an interpretation terminal and electronic medical records, 59 consecutive patients suspected of having new-onset PD from April 2014 to November 2015 who underwent both 123I-MIBG scintigraphy and 123I-ioflupane scintigraphy within 3 months were selected. The inclusion criteria included patients who, according to medical records, (i) had one or two signs of parkinsonian syndrome from among akinesia, tremor, rigidity, and postural reflex disorder, (ii) were aged between 18 and 90 years, (iii) were capable of providing consent, and (iv) underwent both 123I-MIBG and 123I-ioflupane scintigraphy for a definitive diagnosis of PD. The exclusion criteria were patients who (i) had severe infection or poor general condition, (ii) had a medical history of overt cardiac failure or ischemic heart disease that could affect 123I-MIBG scintigraphy, (iii) used drugs that could affect 123I-MIBG and 123I-ioflupane scintigraphy, (iv) had a medical history of overt cerebrovascular disorder, and (v) were suspected of having a disease similar to PD. The final diagnosis of PD was made by a neurologist according to the Parkinson’s Disease Criteria of the UK Parkinson’s Disease Society Brain Bank 8. Patients who had fulfilled the selection criteria and had undergone radionuclide scans but were not definitively diagnosed as having PD by a neurologist were defined as the control group.
Three hours after an intravenous administration of 111–185 MBq of 123I-ioflupane (Nihon Medi-Physics, Tokyo, Japan), two types of scintillation cameras, an ECAM (imaging rate: 18 cm/min, matrix: 256×1024; Canon Medical Systems, Ohtawara, Japan), and a GXA-7200 (imaging rate 17.5 cm/min, matrix 256×1024; Canon Medical Systems), were used to perform single-photon emission computed tomography imaging. A fan-beam collimator was used.
Image reconstruction was performed by successive approximation. In Japan, two software programs for quantitative analysis are available: DaTView (Nihon Medi-Physics, Tokyo, Japan) and DaTQUANT (GE Health Care, Tokyo, Japan) for 123I-ioflupane scintigraphy. In the DaTView analysis, SBR is used as a semiquantitative indicator. In the DaTQUANT analysis, the striatal uptake ratio is used as a semiquantitative indicator. However, there is a high correlation value (r=0.917) between SBR and striatal uptake ratio 9. In our hospital, in reference to the Tossici-Bolt method 10, DaTView was used to calculate SBR. In this scan, SBR was defined as the value of counts in the corpus striatum region of interest divided by that of the entire brain excluding the corpus striatum 10.
Immediately after the intravenous administration of 111 MBq of 123I-MIBG (Fuji RI Pharma, Tokyo, Japan), and 3 h thereafter, two types of scintillation cameras were used to take a planar image (anterior view): ECAM and GXA-7200 (the ekplanation of ECAM and GXA-7200 was overlapping in 123I-ioflupane and 123I-MIBG). A parallel porous collimator for low to mid energy was used. The heart/mediastinum ratio (H/M ratio) was measured using a Smart MIBG (Fuji RI Pharma), in which when the region of interest was set to the heart, the mediastinal region of interest was automatically set to the upper mediastinum. The region of interest was set by an experienced radiologist who set a circular region of interest at the left ventricle.
In this study, the mean value of SBR in the left and right basal ganglia was used. An SBR cutoff value of 3.8 was used to diagnose PD using 123I-ioflupane scintigraphy based on a report stating that 3.8 was the SBR cutoff value for differentiating PD (95% sensitivity, 95% specificity) 11. The delayed-phase cutoff value of the H/M ratio for diagnosing PD using 123I-MIBG scintigraphy was set to 2.2 based on a report stating 1.9–2.8 as the normal range for the H/M ratio and 2.2 as its mean value 12. Finally, on the basis of another report, the SBR×H/M ratio was used to indicate the efficacy of the combined use of 123I-MIBG scintigraphy and 123I-ioflupane scintigraphy 13.
Individual variables were represented as median values. The sensitivity, specificity, positive, and negative predictive values of the SBR value, H/M ratio, and SBR×H/M ratio in diagnosing PD were calculated for all patients, patients with an SBR of less than or equal to 3.8, and patients with an SBR of greater than 3.8.
Continuous variables that were not normally distributed were analyzed using the Mann–Whitney U-test. In all cases, univariate logistic analyses were carried out to determine the associations of age, H/M ratio, SBR value, and the SBR×H/M ratio with the diagnosis of PD. In the groups with SBR less than or equal to 3.8 and greater than 3.8, age-adjusted logistic analyses were carried out to assess the associations of the H/M ratio, the SBR value, and the SBR×H/M ratio with PD diagnosis, and univariate logistic analyses were carried out to assess the associations of age, the H/M ratio, the SBR value, the SBR×H/M ratio, and the group below the SBR×H/M ratio cutoff value with PD diagnosis. An age-adjusted multivariable logistic analysis was carried out for the H/M ratio, the SBR value, the SBR×H/M ratio, and the group below the SBR×H/M cutoff value, respectively. A P value of less than 0.05 was considered significant. All statistical analyses were carried out using the EZR program developed by Jichi Medical University Omiya Hospital (Saitama, Japan) that expanded upon the statistical software R (Auckland University, Auckland, New Zealand).
Of the 59 patients selected, 48 patients were enrolled. On the basis of their medical charts, two patients with cortico-basal degeneration, three patients with drug-induced parkinsonism, one patient with a history of cerebral hemorrhage, and five patients with parkinsonian syndrome that was not definitively diagnosed were excluded. Thirty-seven of the 48 patients enrolled were diagnosed as having PD. Eleven patients who had very mild extrapyramidal findings and did not fulfill the diagnostic criteria of PD were assigned as controls. The clinical backgrounds of the patients and controls are shown in Table 1.
Diagnostic accuracy of each factor in the diagnosis of Parkinson’s disease
Table 2 shows the sensitivity, specificity, and positive and negative predictive values of 123I-ioflupane, 123I-IMBG, 123I-ioflupane, and 123I-MIBG (SBR×H/M ratio) in diagnosing PD in all patients, patients with SBR less than 3.8, and patients with SBR greater than 3.8. Receiver-operating characteristic analysis was used to calculate the diagnostic accuracy rate. PD was predicted by the SBR×H/M ratio. In all patients, the cutoff value was 9.24 and the area under the curve (AUC) was 0.92 [95% confidence interval (CI): 0.85–1] (Fig. 1). In patients with SBR less than 3.8, the cutoff value was 7.82 and the AUC was 0.94 (95% CI: 0.86–1) (Fig. 2). In patients with SBR greater than 3.8, the cutoff value was 12.5 and the AUC was 0.84 (95% CI: 0.62–1) (Fig. 3).
There were 16 patients with SBR greater than 3.8 (eight patients with PD and eight controls). Five of the eight (62.5%) patients with PD had an H/M ratio of less than 2.2, whereas the other three (37.5%) had an H/M ratio of more than 2.2. All eight (100%) control patients had an H/M ratio of more than 2.2.
Logistic regression analyses of various factors related to Parkinson’s disease diagnosis
The results of the logistic regression analyses are shown in Table 3. According to the univariate and age-adjusted analyses in all cases, the H/M ratio, SBR, SBR×H/M ratio, and the group with SBR×H/M ratio less than 9.24 were the factors associated significantly with the diagnosis of PD (P<0.01). In cases with SBR of up to 3.8, neither univariate nor age-adjusted analyses yielded any significant associations. According to univariate logistic analysis of cases with SBR of more than 3.8, the group with SBR×H/M ratio of less than 12.50 was associated significantly with the diagnosis of PD (P=0.024), whereas the other variables were not. In the age-adjusted logistic analysis of cases with SBR more than 3.8, the SBR value, the value of SBR×H/M ratio, and the group with SBR×H/M ratio less than 12.50 were associated significantly with PD diagnosis (P<0.05), whereas the H/M ratio was not.
The combined use of 123I-MIBG and 123I-ioflupane scintigraphy has been reported in a previous study involving 72 cases of PD and related diseases 14. The sensitivities of 123I-MIBG and 123I-ioflupane scintigraphy were each 70% when used alone and increased to 98% when used in combination. In 11 patients initially suspected of SWEDD (scans without evidence of dopaminergic deficits), but finally diagnosed as having PD, eight patients showed an H/M ratio of less than 2.2 and nine showed a washout rate above 30% 15. Thirty-four patients who received 123I-MIBG and 123I-ioflupane scintigraphy during a period ranging from 3 to 4 months showed mild accuracy in differentiating PD from non-PD (123I-MIBG 67.6%; 123I-ioflupane 67.6%) 16. However, with the combination of 123I-MIBG (cutoff value: delayed H/M ratio 2.745) and 123I-ioflupane (cutoff value: SBR 3.24), they showed 79.4% accuracy in differentiating PD from non-PD 16. Moreover, the combined use of 123I-MIBG and 123I-ioflupane scintigraphy can help distinguish the patients with essential tremor from those with PD and parkinsonism 17. However, the onset periods of the cases were not constant in the study. Another report with 18 patients suspected of having early-stage PD showed that the diagnostic ability of 123I-MIBG and 123I-ioflupane scintigraphy increased when used in combination 7. However, that study did not carry out a detailed analysis of the results of each test separately.
Our study investigated the significance of using 123I-MIBG scintigraphy alone, 123I-ioflupane scintigraphy alone, and both combined in the diagnosis of new-onset PD. Moreover, this is the first study, to our knowledge, to report cases of suspected early PD excluding cases with diagnoses other than PD, and the first to use patients without a definitive diagnosis as the control group for comparison. The sensitivity of 123I-ioflupane scintigraphy alone was found to be 0.78 (0.62–0.92) and that of 123I-MIBG scintigraphy alone was 0.65 (0.48–0.80). The sensitivity of the combination of both was 0.81 (0.65–0.92).
When PD is suspected, 123I-ioflupane with its higher sensitivity is the preferred, cost-effective, initial test. However, there is no report that details the diagnosis of PD when 123I-ioflupane scintigraphy did not meet the cutoff value. In our study, in patients with SBR of at least 3.8, the AUC was 0.84 with the combined use of 123I-MIBG scintigraphy when the SBR×H/M ratio was used. The group with SBR×H/M ratio of less than 12.50 when additionally adjusted for age showed a statistically significant odds ratio of 25.5. The results of our study suggested that 123I-MIBG scintigraphy in addition to 123I-ioflupane scintigraphy is useful in cases where the SBR greater than 3.8.
The patients in our study were patients who had been ill for a short period of time and were in the initial stages of the disease. In this situation, particularly when the SBR×H/M ratio was less than 12.50, careful observation of clinical signs was considered important. Age-adjusted logistic analysis showed that the combined use of the two types of scintigraphy might improve the diagnostic accuracy and, thereby, prevent missing the diagnosis of PD in cases with high SBR values.
Although temporal changes seen on 123I-MIBG scintigraphy or 123I-ioflupane scintigraphy can individually be used as tools for achieving a definitive diagnosis, early assessments by combining both tests are preferred for the early diagnosis and treatment of PD.
The general pathological progression of PD that has been proposed is Braak’s theory, in which α-synuclein deposition occurs in the dorsal nucleus of the vagus nerve and the olfactory bulb and gradually progresses through the brainstem to the cerebral neocortex 18. However, in another report, the disease progression was consistent with Braak’s theory in only half the patients 19 and varied markedly between patients. In our study, there were some patients who had a low H/M ratio and a high SBR value in PD patients. This reason is difficult, but we think there are several pathological pathways in PD disease.
The concept of a PD-at risk syndrome with stages before the onset of motor symptoms in PD has been proposed 20 in which the syndrome is classified as prephysiological, preclinical, premotor, prediagnostic, and PD 21.
The diagnosis of PD primarily depends on physical findings. Although a decreased concentration of α-synuclein in the spinal fluid has been used as a biochemical marker for the early-stage diagnosis of PD, it requires a lumbar puncture, which is an invasive procedure 22. However, diagnostic imaging with nuclear medicine is objective and noninvasive, and the combination of myocardial sympathetic nerve scintigraphy and DAT scintigraphy is expected to be useful for diagnosing PD in its early stages.
This study had several limitations. First, the patients in this study were from a single facility and only a small number of cases could be studied. Second, the relationships between sex, clinical signs, severity, and 123I-MIBG or 123I-ioflupane scintigraphy were not considered; thus, the characteristics of the diagnostic imaging on the basis of objective clinical findings could not be determined. Third, bias occurred in the assessment of the definitive diagnosis. Because mild signs of parkinsonism were difficult to detect, the detection rate was affected. Fourth, normal controls were not obtained, Finally, the marker used was semiquantitative. In the future, a more accurate normal range for database verification is desired.
The results of this study suggest that if the SBR is above 3.8, using the SBR×H/M ratio can enable the diagnosis of PD, implying that the combined use of 123I-MIBG and 123I-ioflupane scintigraphy is advantageous in diagnosing new-onset PD.
The authors express their deepest thanks to Dr. Tsutomu Kamo of Noborito Internal Medicine/Cranial Nerve Clinic who cooperated in this research.
Authors’ contributions: Yukinori Okada, Makoto Shiraishi, and Hisao Nakamura had the original idea and collected and analyzed the data. Futaba Maki, Naoshi Sasaki, and Oga Sasaki checked and suggested the clinical diagnosis. Yasuhiro Hasegawa and Yasuo Nakashima suggested the data analysis methods and checked the data analysis results.
Conflicts of interest
There are no conflicts of interest.
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