SPECT Molecular Imaging in Parkinson's Disease

3.1. The Course and the Pathogenesis of PD

Brain SPECT imaging of DAT with specific radioligands provides a useful tool of in vivo investigation of the pathogenesis of PD, and it is a sensitive method for examining the integrity of the presynaptic dopaminergic system [15]. Cerebral and extracranial Lewy-body-type degeneration in PD does not develops independently from each other but develop in a strongly coupled manner. The cerebral and extracranial changes are driven by at least similar pathomechanisms [31]. Patients with PD have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression [32], whereas postsynaptic striatal D2 receptors are upregulated [33]. Similarly, another study reported that the mean ¹²³I-IBZM striatal-occipital ratio of binding was significantly higher in PD patients than in controls. In PD patients, higher values were found contralateral to the clinically most affected side, suggesting D2 receptor upregulation and the reverse was seen using ¹²³I-FP-CIT SPECT [34]. Dual isotope imaging using ⁹⁹Tc^m-TRODAT-1 and ¹²³I-IBZM is also a useful means in evaluating the changes of both pre- and postsynaptic dopamine system in a primate model of parkinsonism [35].

There was a significant association of visually analyzed shapes of the striatum in FP-CIT SPECT and clinical PD subtype. It suggested that factors other than nigrostriatal degeneration may contribute to disease severity [36]. One study including 122 patients confirmed neuropathological models for reduced dopaminergic projection to the dorsal putamen in akinetic-rigid patients as well as the lateral putamen and caudate nucleus in tremor-dominant patients in vivo [37], and the serotonergic system is suggested to be implicated in PD [38]. Furthermore, another study showed that SERT-dependent ¹²³I-FP-CIT uptake may allow a more comprehensive assessment of neurochemical disturbances in degenerative parkinsonisms [39]; this study suggested that the neurodegenerative process extends beyond nigrostriatal system and affects serotoninergic neurons in parkinsonisms.

3.2. Early Diagnosis of PD

Since the in vivo molecular imaging techniques using SPECT have been introduced, the diagnosis of PD became more reliable by assessing dopaminergic and even nondopaminergic systems. SPECT is a very sensitive technique to detect nigrostriatal degeneration in PD. Various radiotracers have been used in the diagnosis of PD. DAT imaging is abnormal even in the earliest clinical presentation of PD [15]. A study using ¹²³I-β-CIT found that the relative uptake reduction in the hemi-PD patients was greater in the putamen than in the caudate in patients with early PD and suggested that it may be useful in identifying individuals with developing dopaminergic pathology before onset of motor symptoms [40].

It was reported that ¹²³I-β-CIT SPECT was 100% sensitive and specific for the diagnosis in younger patients (age <55 years). In older patients (age >55 years), specificity was substantially lower (68.5%) [41]. More recently, a prospective, longitudinal study using ¹²³I-FP-CIT had investigated 99 patients with tremor and/or parkinsonism over 3 years, and the results showed a mean sensitivity of 78% and a specificity of 97% [42]. A 2-year followed-up SPECT study using ⁹⁹Tc^m-TRODAT-1 was performed in patients with clinically unclear Parkinsonian syndromes (CUPSs) and found that the rate of disagreement of SPECT in the patients was of 20%. The sensitivity of this technique was 100%, and specificity was 70%. It indicated that TRODAT-1 helps the diagnosis of patients with CUPS [43]. DAT SPECT is sensitive enough to detect a loss of nigrostriatal neurons in vivo even in preclinical phases of sporadic PD.

¹²³I-FP-CIT SPECT has been successfully used to detect the loss of dopaminergic nigrostriatal neurons in Parkinson's disease at an early stage. But the results reported were controversial. Tissingh et al. reported that striatal ¹²³I-FP-CIT uptake is markedly decreased in PD, more in the putamen than in the caudate nucleus, and the mean reduction in the putamen and caudate nucleus was 57% and 29% of the control mean, respectively. However, no significant correlations were found between striatal ¹²³I-FP-CIT binding ratios and disease severity [20]. Spiegel et al. found that the striatal FP-CIT binding correlated significantly with the motor part of the unified Parkinson's disease rating scale (UPDRS) but not with age, disease duration, or gender [44]. Another study indicated that in patients with PD, the striatum, caudate, and putamen uptake was correlated with disease severity assessed by UPDRS and duration of disease [36]. More studies are needed to confirm these findings.

⁹⁹Tc^m-TRODAT-1 study including 29 patients with early PD and 38 healthy volunteers found that compared to controls, the uptake in caudate and anterior and posterior putamen values were significantly decreased in PD patients (Figure 1). Using the posterior putamen as the main region of interest resulted in the greatest accuracy sensitivity 79% and specificity 92% [45]. Patients with unilateral PD showed a bilateral loss of striatal DA transporters [46]. A study using semiquantitative ¹²³I-FP-CIT SPECT detected a bilateral dopaminergic deficit in early PD with unilateral symptoms and preclinical DAT loss in the ipsilateral striatal binding, corresponding to the side not yet affected by motor signs. It suggested that semi-quantitative analysis may be used to diagnose PD at early stage as well as to identify individuals developing bilateral dopaminergic damage [47]. The decrease of striatal uptake contralateral to the more affected side of the body was more prominent compared to the ipsilateral side [48]. Moreover, another study showed a significant loss of putaminal uptake ipsilateral to the symptoms was found in the stage I group compared with the healthy volunteers [49]. The mean reduction of binding was found in the order of putamen and caudate nucleus.

DAT imaging is a sensitive method to detect presynaptic dopamine neuronal dysfunction. Normal DAT-SPECT can be used to exclude underlying true nigrostriatal dysfunction [50].

SPECT also contributes to the assessment of the nonmotor symptoms of PD. MIBG was used in the diagnosis of damaged tissue of the heart. However, Sawada et al. [43] found that a reduction in MIBG cardiac accumulation reflects the systemic pathological process of the disease. Both early and delayed images showed that the heart to mediastinum ratios were significantly lower in the PD group than in the non-PD group [51].

Sakakibara et al. [52] first reported the correlation of urinary dysfunction with nigrostriatal dopaminergic deficit in PD, which was studied by ¹²³I-β-CIT SPECT. The tracer uptake in patients with urinary dysfunction was significantly reduced than in those without urinary dysfunction

3.3. Differential Diagnosis of PD

Clinical features of PD may be shared with other disorders; thus, the differential diagnosis of PD is extensive. Idiopathic Parkinson's disease is associated with Lewy body degeneration of nigrostriatal dopaminergic neurons [53]. Atypical parkinsonian syndromes (APSs) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration are characterized by poor response to antiparkinsonian medication and rapid clinical deterioration, which one often confused with PD. Other diseases, for example, drug-induced parkinsonism (DIP), essential tremor (ET), vascular parkinsonism (VP), or Dementia with Lewy bodies (DLBs) may also share common features with PD.

ET is a slowly progressive neurological disorder. DIP is developed when patients are treated with neuroleptic or dopamine receptor blocking agents. In most patients, Parkinsonism is reversible upon stopping the offending drug, though it may take several months to resolve fully but in some patients it may even persist. The differentiation between PD and DIP is difficult to assess on clinical grounds alone.

Functional imaging of the DAT defines integrity of the dopaminergic system, and a normal scan suggests an alternative diagnosis such as ET, VP (unless there is focal basal ganglia infarction), DIP, or psychogenic parkinsonism [17, 54]. Furthermore, a semiquantitative analysis with a cut-off of striatal asymmetry index greater than 14.08 could differentiate PD from VP with a 100% specificity [55]. ¹²³I-FP-CIT SPECT images demonstrate that SPECT imaging with DAT ligands is useful to determine whether parkinsonism is entirely drug induced [56] and showed high levels of accuracy [57]. Cuberas-Borrós et al. performed FP-CIT images in 3 different groups of ET, DIP, and PD patients. Lower uptake was found in the PD group in comparison with the ET and DIP groups both in the putamen and in the caudate nucleus, but the differences between DIP and ET populations were only found in the putamen. There was an optimal discrimination threshold value between the reference population and the pathologic population for the putamen ratio by using volumes of interests, (VOIs) analysis [58].

SERT-dependent ¹²³I-FP-CIT imaging showed a mild decrease in SERT levels in PD compared to ET and health control, and reduced to undetectable levels of SERT in PSP and DLB patients were displayed markedly [39]. To improve diagnostic accuracy, non-DAT tracers (i.e., D2 dopamine receptors) are necessary together with long-term clinical follow-up and rescans [59].

MSA is a neurodegenerative disorder characterized by neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures [60]. Clinically, MSA is characterized by autonomic dysfunction and/or urinary dysfunction which may be associated with parkinsonian symptoms in 80% of patients (MSA-P) or with cerebellar ataxia in 20% of patients (MSA-C). It is difficult to differentiate it from other movement disorders, particularly in the early course of disease. Voxel wise analysis of ¹²³I-β-CIT SPECT revealed more widespread decline of monoaminergic transporter availability in MSA-P compared with idiopathic Parkinson's disease (IPD) [61], matching the underlying pathological features. They suggest that the quantification of midbrain DAT signal should be included in the routine clinical analysis of ¹²³I-β-CIT SPECT in patients with uncertain parkinsonism.

A combined ^99mTc-ECD/¹²³I-FP-CIT brain SPECT protocols have been proven to improve the differential diagnosis of IPD and MSA as well as corticobasal degeneration and PSP [62]. SPECT with the tracer ¹²³I-Ioflupane can also give an accurate and highly sensitive measure of dopamine degeneration [63].

A study showed that the degree of loss was higher in putamen than caudate in both PD and MSA patients. However, MSA patients showed a more symmetric loss (ipsilateral versus contralateral side) of striatal DAT in both caudate and putamen than PD patients (Figure 2) [64]. It was also reported that patients with a side-to-side difference of reduced striatal ¹²³I-β-CIT binding greater than 15% are likely to suffer from IPD, while the patients with the difference between 5% and 15% are more likely to have MSA [65]. Another study showed that mean distribution volume ratios (DVRs) in the basal ganglia of MSA patients were significantly less than in controls, but generally higher than in PD patients. Furthermore, the MSA patients had significantly increased DVRs in the posterior putamen (mean 0.49 ± 0.30) compared with PD patients (0.74 ± 0.25) [66].

Another study which used both ¹²³I-β-CIT (for DAT) and ¹²³I-IBF (for D2) reported that DAT binding in the posterior putamen was markedly reduced in all patients. However, D2 binding in posterior putamen was significantly increased in dopa-untreated PD, and it was significantly reduced in MSA. These findings suggested that DAT SPECT may be useful in differentiating parkinsonism from controls and D2 SPECT in further differentiating MSA from PD [67]. IBZM SPECT using recently introduced three dimensional automated quantification method calculating the Striatal/frontal cortex binding ratios [68] and voxel-by-voxel binding potential parametric imaging also can discriminate among extrapyramidal diseases such as PD and PSP [69].

¹²³I-IBZM SPECT is an effective diagnostic tool in the establishment of the differential diagnosis in patients with PD and Parkinson-plus syndromes. Quantification of these studies had limited utility since the overlapping of index values between normal and pathological restricts their use in individual cases [70]. Vlaar et al. reported that FP-CIT SPECT is accurate to differentiate patients with IPD from those with ET, and IPD from VP and DIP, but the accuracy of both FP-CIT and IBZM SPECT scans to differentiate between IPD and APS is low [54]. However, a study suggested that using multidimensional combination of FP-CIT, IBZM, and MIBG scintigraphy was likely to significantly increase test accuracy (94%) in differentiating PD from APS [71]. More recently, a study using ¹²³I-PE21 indicated that dopamine transporter scan has a high sensitivity and specificity in distinguishing between patients with and without striatal neurodegeneration. Calculation of the striatal anterior-posterior ratio can assist in differentiating between idiopathic PD and APS [72]. Moreover, study with ¹²³I-FP-CIT in165 patients with a clinical diagnosis of PD (n = 120) or APS (n = 45) suggested that a global and severe degeneration pattern had a high positive predictive value of APS within the first 5 years of the disease [73].

A ¹²³I-FP-CIT and ¹²³I-IBZM SPECT study, in which seven subjects were all from a Spanish family with G309D mutation in the PINK1 gene, showed that striatal DAT binding was reduced in all three PARK6 patients. But in two of the siblings, DAT binding was markedly increased. It suggested that the increased DAT binding may be an early preclinical finding [74]. SPECT is also useful for distinguishing PD from Dopa responsive dystonia (DRD), or for assessing the integrity of the nigrostriatal dopaminergic pathway in atypical cases of postural tremor or iatrogenic parkinsonian syndromes. The imaging with ⁹⁹Tc^m-TRODAT-1/¹²³I-IBZM in a 39-year-old woman with a 24-year history of DRD indicated that ⁹⁹Tc^m-TRODAT-1 is helpful in differentiating DRD from early-onset idiopathic parkinsonism and the ¹²³I-IBZM SPECT is also helpful in differentiating these two conditions in the later clinical course [75].

In IPD, two different clinical phenotypes are usually distinguished: a tremor-dominant variant (TD) and an akinetic-rigid type (ART). TD patients compared to ART patients are characterized by a slower disease progression and a minor cognitive impairment. For different phenotypes of PD, ¹²³I-FP-CIT SPECT has indicated that the dopaminergic system in ART patients is more involved compared to that in the TD patients and that this kind of difference is present from the initial stage of the disease [76–78]. There was a significantly higher FP-CIT uptake in contralateral putamen and a higher but not statistically significant uptake in all the other striatal regions in TD patients when compared to ART patients [77]. Similarly, Spiegel et al. reported a greater impairment in ART patients in all striatal regions analyzed [78]. These results suggest that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

3.4. Monitoring the Progression of the PD

Pathologic studies investigating the rate of PD progression have been limited to patients with severe illness of long duration and rely entirely on cross-sectional data. The UPDRS or other functional clinical endpoints are used to monitor disease progression. It makes it difficult to isolate clinical change solely due to disease progression [79].

The rate of progression of dopaminergic degeneration is much faster in PD than in normal aging [80]. Patients with PD present first with unilateral symptoms that gradually progress to involve both sides [6]. Clinical progression has been investigated with SPECT, which could prove to be an objective tool for monitoring the disease progression.

¹²³I-β-CIT SPECT imaging of the dopamine transporter is a sensitive biomarker of PD onset and severity. A group of 50 early-stage PD patients was examined [81]. Two SPECT imaging series were obtained 12 months apart. The average decrease in ¹²³I-β-CIT binding ratios was about 8% in the whole striatum, 8% in the putaminal region, and 4% in the caudate region. This finding supported the feasibility of using ¹²³I-β-CIT in the evaluation of disease progression in PD [82]. Moreover, sequential SPECT scans using ¹²³I-β-CIT in PD subjects demonstrated a decline in striatal uptake of approximately 11.2%/year from the baseline scan, compared with 0.8%/year in the healthy controls [79]. Another SPECT study with ¹²³I-β-CIT demonstrated a rapid decline of striatal binding in patients with APS, exceeding the reduction in PD, and the dopaminergic degeneration in PD slows down during the course of the disease [83].

Combined ¹²³I-β-CIT and ¹²³I-IBZM SPECT studies have demonstrated that postsynaptic dopamine receptor upregulation contralateral to the presenting side occurs in untreated unilateral PD and disappears in untreated bilateral (asymmetric) PD despite a greater loss of dopamine transporter function [84]. This may be helpful in monitoring the progression of nigrostriatal dysfunction in early PD. Tatsch et al. [21] found that specific ¹²³I-IPT uptake in the caudate and putamen, and putamen to caudate ratios, decreased with increasing Hoehn and Yahr stage (H-Y). These findings indicated that ¹²³I-IPT SPECT also may be a useful technique to estimate the extent of nigrostriatal degeneration in PD patients.

Tissingh et al. reported that disease severity correlated negatively and highly significantly with the ¹²³I-β-CIT binding in patients with early PD. Tremor ratings did not correlate with the ¹²³I-β-CIT uptake, whereas rigidity and bradykinesia did [46]. The striatal ¹²³I-β-CIT uptake in a large cohort of PD subjects significantly correlated with severity of PD as measured by UPDRS [79]. The mean reduction of ⁹⁹Tc^m-TRODAT-1 uptake was found in the order of putamen (contralateral side, −81%; ipsilateral side, −67%) and caudate nucleus (contralateral side, −46%; ipsilateral side, −40%), and it correlated negatively with the UPDRS and H-Y staging [85].

Winogrodzka et al. [80] used ¹²³I-FP-CIT SPECT for the assessment of the rate of dopaminergic degeneration in PD. The mean annual decrease in striatal binding ratios in PD patients was found to be about 8% of the baseline mean, indicating that ¹²³I-FP-CIT SPECT was applicable to investigate the progression of dopaminergic degeneration. The specific to nonspecific ¹²³I-FP-CIT uptake ratios were calculated for striatum, caudate, and putamen, all of which were correlated with disease severity assessed by UPDRS and the duration of disease, suggesting that tremor may origins from other systems instead of the dopamine transporter system. Meanwhile, these ratios correlated with the bradykinesia subscore but not with rigidity or tremor subscore. It suggested that factors other than nigrostriatal degeneration may contribute to disease severity [36].

3.5. Evaluation of the Treatment Effect of PD

Current therapies include drug therapy, surgical procedures, and stem cell transplantation. Drug therapy such as DA replacement therapy with levodopa fails to prevent the progression of the disease process and only alleviates the clinical symptoms. Once the diagnosis is made, the neurologist with the patient must decide whether to institute treatment at the time of diagnosis or when functional disability occurs [86]. To evaluate the effectiveness of treatment, it is critical to develop methods that can reliably measure the progression of dopaminergic degeneration.

Postsynaptic imaging has been helpful in predicting therapeutic response to dopaminergic medication early in the course of Parkinson's disease. Studies have demonstrated that PD patients receiving treatment do better than those who do not, and those receiving treatment earlier do better in long term [87]. Schwarz et al. performed a follow-up study of 2–4 years including 55 patients with parkinsonism and prior dopaminomimetic therapy and found that IBZM-SPECT accurately predicted the response to apomorphine and levodopa, The sensitivity/specificity was 96.3%/64.7%, and 100%/75% [88]. Thus, ¹²³I-IBZM can be used routinely to identify which PD patients will benefit from dopaminergic medication [89]. Another study including 20 PD patients who undergone short-term levodopa test and SPECT imaging found there was a relationship between responsiveness to levodopa and asymmetry detected with ¹²³I-FP-CIT. This technique can predict dopaminergic responsiveness in patients with PD [90].

Recently, a ⁹⁹Tc^m-TRODAT-1 SPECT indicated that levodopa did not interfere with DAT binding, suggesting that differences between clinical assessment and radiotracer imaging in clinical trials may not be specifically related to levodopa treatment [91]. Similarly, the effect of subchronic treatment on striatal DAT was examined in patients who were not currently being treated with these medications. These results suggested that typical clinical doses of levodopa/carbidopa and L-selegiline did not induce significant occupancy of the ¹²³I-β-CIT binding site and that 4–6 weeks of treatment caused no significant modulation of DAT levels. These results supported the validity of measuring DAT levels with ¹²³I-β-CIT without the need to withdraw patients from medication treatment [92]. ¹²³I-β-CIT SPECT imaging provides a quantitative biomarker for the progressive nigrostriatal dopaminergic degeneration in PD. As new protective and restorative therapies for PD are developed, dopamine transporter imaging offers the potential to provide an objective endpoint for these therapeutic trials [79, 80].

Hwang et al. found that the PD patients with fluctuating levodopa response showed a significant decrease in ¹²³I-IBZM uptake (D2 receptor densities) than early levodopa-naive PD and chronic PD with stable levodopa response [93], which contributed to the development of motor fluctuation.