Neurol Sci (2010) 31:417–422 DOI 10.1007/s10072-010-0239-z
REVIEW ARTICLE
Recent developments in innervation imaging using iodine-123-metaiodobenzylguanidine scintigraphy in Lewy body diseases Giorgio Treglia • Ernesto Cason • Anna Gabellini Alessandro Giordano • Giorgio Fagioli
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Received: 20 August 2009 / Accepted: 5 February 2010 / Published online: 10 March 2010 Ó Springer-Verlag 2010
Abstract Radiolabeled metaiodobenzylguanidine (MIBG) is an analog of guanethidine and is taken up by the postganglionic presynaptic nerve endings. MIBG uptake in the heart correlates with adrenergic function, which can be reduced in Lewy body diseases. We described the recent developments in innervation imaging using 123I-MIBG scintigraphy in Lewy body diseases including Parkinson’s disease and dementia with Lewy bodies. Particularly, we underlined the role of MIBG scintigraphy in differential diagnosis of movement disorders. As described by recent studies, MIBG scintigraphy is a valuable diagnostic tool for differentiation between Lewy body diseases and parkinsonian syndromes or other movement disorders with parkinsonism. Furthermore, this method may provide a powerful differential diagnostic tool between dementia with Lewy bodies and Alzheimer’s disease. We also reported the results of clinical investigations about the correlation between characteristics of Parkinson’s disease and myocardial MIBG uptake. Keywords Metaiodobenzylguanidine Lewy body diseases Innervation imaging Movement disorders Parkinson’s disease
G. Treglia (&) E. Cason G. Fagioli Nuclear Medicine Unit, Maggiore Hospital Bologna, Largo Nigrisoli 2, 40133 Bologna, Italy e-mail:
[email protected] A. Gabellini Neurology Unit, Maggiore Hospital Bologna, Bologna, Italy A. Giordano Nuclear Medicine Institute, Policlinico Gemelli Roma, Universita` Cattolica del Sacro Cuore, Rome, Italy
Introduction Radiolabeled metaiodobenzylguanidine (MIBG) is considered an established sympathetic neuron imaging agent useful to study the organs richly innervated by the sympathetic nervous system [1, 2]. MIBG is an analog of guanethidine and is taken up by the postganglionic, presynaptic nerve endings. After depolarization, MIBG is released into the synaptic cleft like norepinephrine but is not metabolized. MIBG uptake has been shown to correlate with adrenergic innervation. Furthermore, there is evidence that MIBG uptake is also dependent on the functional integrity of the adrenergic system [1, 2]. Previous studies have applied MIBG innervation imaging in patients with various cardiac diseases: arrhythmias, coronary artery disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, hearth transplantation and druginduced cardiomyopathy [1, 3, 4]. Also Lewy body diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), present an impairment of adrenergic function and consequently an abnormal MIBG innervation imaging [2]. This review describes the recent developments regarding MIBG innervation imaging in Lewy body diseases. Imaging method Before the examination, it is necessary to know whether the patient has taken drugs that can interfere with MIBG uptake. Indeed it is necessary to establish an interfering drug withdrawal for an appropriate period of time taking into account their biological half-lives [1]. After thyroid blockage, 111 MBq of 123I-MIBG is intravenously administered at rest and early and delayed
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Fig. 1 Interpretation of 123IMIBG scintigraphic findings in differential diagnosis between Lewy body disease (LBD) and other movement disorders
images are obtained from 15 to 30 min later and from 3 to 4 h later, respectively. Planar images with anterior view are adequate for the evaluation of cardiac sympathetic function in Lewy body diseases (Figs. 1, 2, 3, 4, 5). The most common index used for imaging interpretation is the heart to mediastinum ratio (H/M ratio) that represents a simple semi-quantitative measure. Regions of interest (ROIs) are set in the heart (H) and the mediastinum (M) to obtain the mean count in each ROI, after which the H/M ratio is calculated. Based on the resulting ratio, the degree of cardiac uptake is evaluated: a H/M ratio higher than 1.75 is considered normal by most authors [1, 2]. MIBG and extrapyramidal system neurological diseases In recent years, it has been revealed that Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) share one clinicopathological entity: Lewy body diseases (LBD) has thus become a general term for these diseases [5]. Based on the information obtained thus far, the markedly decreased MIBG uptake in the heart is considered to be a specific finding of LBD [6] (Figs. 3, 5). Decreased cardiac uptake of MIBG has been reported in the early stages of PD; this finding suggests that degeneration of the cardiac sympathetic nerve early begins in the disease process of PD and that it occurs before neuronal cell loss in the dorsal vagal nucleus [7]. Mitsui et al. [8] provided further evidence that the markedly decreased cardiac uptake of MIBG observed in PD cases represents preferential involvement of the cardiac sympathetic nerve plexus in this disorder.
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Fig. 2 Normal uptake pattern of 123I-MIBG scintigraphy (anterior view at 4 h after injection of 111 MBq); the uptake of the radiopharmaceutical in salivary glands, liver, heart and lungs is considered as physiological (Image from Nuclear Medicine Unit of Maggiore Hospital of Bologna, Italy)
According to the clinical criteria, it might be difficult to prove the diagnosis of PD in patients with slight symptoms and in these cases, 123I-FP-CIT SPECT and 123I-MIBG scintigraphy may contribute to the early diagnosis of PD. An impairment of nigrostriatal dopaminergic and myocardial sympathetic systems in most of the patients has been shown even in the earliest clinical stage of PD [9]. In addition, the functional loss of nigrostriatal and cardiac sympathetic neurons seems to be coupled closely but the
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Fig. 3 An anterior view at 4 h after injection of 111 MBq of 123 I-MIBG. MIBG scintigraphy was performed in a patient with cognitive impairment for differential diagnosis between dementia with Lewy bodies and other neurodegenerative diseases with cognitive impairment. No uptake of the radiopharmaceutical was observed in the heart suggesting a Lewy body disease (LBD) (Image from Nuclear Medicine Unit of Maggiore Hospital of Bologna, Italy)
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Fig. 5 An anterior view at 4 h after injection of 111 MBq of 123 I-MIBG. MIBG scintigraphy was performed in a patient with parkinsonism for differential diagnosis between Parkinson’s disease and other parkinsonian syndromes: no uptake of the radiopharmaceutical is observed in the heart suggesting a Parkinson’s disease (PD) (Image from Nuclear Medicine Unit of Maggiore Hospital of Bologna, Italy)
(including PD and DLB) and parkinsonian syndromes or between LBD and other movement disorders with parkinsonism (Figs. 1, 2, 3, 4, 5). Differential diagnosis between LBD and parkinsonian syndromes
Fig. 4 An anterior view at 4 h after injection of 111 MBq of 123 I-MIBG. MIBG scintigraphy was performed in a patient with parkinsonism for differential diagnosis between Parkinson’s disease and other parkinsonian syndromes: the uptake of radiopharmaceutical observed in the heart was normal excluding a Parkinson’s disease (PD) (Image from Nuclear Medicine Unit of Maggiore Hospital of Bologna, Italy)
reasons for this phenomenon remain unclear [9]. The severity of this impairment depends on disease progression and treatment: MIBG and FP-CIT uptake in PD decrease gradually with an increase in disease severity [9, 10].
Role of myocardial MIBG scintigraphy in differential diagnosis of movement disorders As described by recent studies MIBG is a valuable diagnostic tool for differentiation between Lewy body diseases
Kashihara et al. performed myocardial 123I-MIBG scintigraphy in patients with PD, DLB and PAF and compared the results with those of patients with other neurodegenerative disorders presenting extrapyramidal symptoms such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and multiple-system atrophy (MSA) and with those of control patients. The authors found that myocardial 123I-MIBG uptake is reduced from sympathetic nerve terminals in Lewy body diseases. Because this reduction occurs earlier during these diseases, their time of appearance may prove a sensitive way to differentiate LBD from other neurodegenerative disorders that present with extrapyramidal or autonomic dysfunction [11]. Based on a meta-analysis of 246 cases of PD and 45 cases of MSA, Braune reported an overall sensitivity of MIBG scintigraphy to identify PD of 89.7% and a specificity to discriminate patients with PD from patients with MSA of 94.6% [2, 12]. In a recent study of Sawada et al. [13], sensitivity and specificity of MIBG scintigraphy in detection of PD were 84.3 and 89.5%, respectively. MIBG scanning was reported to be more reliable in the differential diagnosis between PD and MSA than clinical autonomic testing with a sensitivity of 80% and a specificity of 100% [14–16].
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Differential diagnosis between LBD and other movement disorders with parkinsonism (vascular parkinsonism, essential tremor, drug-induced parkinsonism) Kim et al. performed myocardial MIBG scintigraphy to prospectively evaluate sympathetic dysfunction in patients with cerebrovascular disease who develop clinical symptoms of vascular parkinsonism (VP). The authors reported that myocardial sympathetic dysfunction found in PD is absent in most patients with VP. Therefore, MIBG innervation imaging may be useful to help distinguish between PD and VP patients in clinical practice [17]. In some cases, it is difficult to differentiate essential tremor (ET) from Parkinson’s disease (PD), especially in the early stages of the disease. The study of Lee et al. demonstrated that cardiac MIBG uptake in patients with ET is within the normal range and clearly distinguishes them from patients with PD. Therefore, cardiac MIBG scintigraphy is a useful, readily available method for differentiating ET from PD [18]. Cardiac sympathetic dysfunction was investigated using MIBG myocardial scintigraphy in patients with druginduced parkinsonism (DIP). Myocardial MIBG uptake was significantly greater in patients with DIP than in those with PD. MIBG uptake was not different between the DIP patients and controls. Patients with DIP whose MIBG uptake lay within the normal range showed dramatic improvement or complete resolution of parkinsonism on clinical follow-up after withdrawal of the offending drug, whereas DIP patients whose MIBG uptake was significantly reduced had persistent parkinsonism and these patients responded well to treatment with levo-DOPA. It is speculated that in these patients with DIP and reduced MIBG uptake the offending drugs may have aggravated the potential dopaminergic defect and thus unmasked the clinical manifestation of PD [19]. Differential diagnosis between DLB and Alzheimer’s disease (AD) Several single-center studies using MIBG scintigraphy have demonstrated reduced cardiac MIBG uptake in DLB, as opposed to AD, with excellent sensitivity and specificity [20–23]. Particularly, this method may provide a powerful differential diagnostic tool when it is difficult to distinguish cases of DLB from AD using brain perfusion scintigraphy [24]. In a recent study Estorch et al. reported that cardiac MIBG uptake was significantly decreased in patients with DLB in comparison to all other neurodegenerative diseases with cognitive impairment with a sensitivity of 94% and a specificity of 96% [25].
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If these findings will be confirmed in multicentre studies with a large number of patients, MIBG scintigraphy may emerge as a useful tool in the early discrimination of DLB from AD. Nevertheless, to date, the most compelling evidence has come from visualization of striatal dopamine transporter activity, using 123 I-FP-CIT [20]; this marker has demonstrated high sensitivity and specificity in a large multicenter trial (sensitivity of 78% and specificity of 90% for probable DLB versus non-DLB dementia) [26] and in a small study with pathological confirmation of diagnosis (sensitivity of 88% and specificity of 100%) [27], supporting the usefulness of this test in distinguishing DLB from AD. An advantage of cardiac MIBG scintigraphy over other functional studies is the short acquisition time and comfortable planar imaging, which is appreciated by patients and their caregivers [25]. Differences in cardiac MIBG uptake between PD and DLB A recent report compared MIBG findings in PD and DLB during the early disease stage: MIBG uptake in the heart was more compromised in DLB than in PD, suggesting the usefulness of MIBG in early diagnosis as well [28]. This finding is probably caused by the loss of postganglionic sympathetic nervous function, although dysautonomia in some patients with DLB may result from preganglionic dysfunction too [29].
Correlation between characteristics of PD and myocardial MIBG uptake Regarding the correlation between genetic or clinical characteristics of PD and MIBG uptake more detailed investigations have been undertaken. In their study Quattrone et al. showed that cardiac sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. These authors also demonstrated that MIGB uptake has a heterogeneous pattern in genetic PD, because it was differently impaired in patients with different mutations in the same gene or with the same gene mutation [30]. In idiopathic PD, different clinical subtypes are distinguished due to predominant motor symptoms: a tremordominant type, an akinetic-rigid type, and a mixed type. Spiegel et al. compared myocardial sympathetic innervation, measured by MIBG scintigraphy, in different subtypes of PD at early and advanced stages. At all stages, myocardial MIBG uptake was significantly higher in tremor-dominant patients than in the other two categories. Furthermore, at each stage, myocardial MIBG uptake correlated significantly with severity of hypokinesia and rigidity, but not with severity of resting or postural tremor [31].
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Clinical symptoms of PD include not only motor distress, but also autonomic dysfunction. MIBG findings show that cardiac postganglionic sympathetic dysfunction in patients with PD is already present in early disease without clinical evidence of autonomic dysfunction. Furthermore, MIBG myocardial uptake is sometimes impaired in PD even in the absence of abnormal findings on autonomic testing, suggesting that MIBG myocardial scintigraphy is more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction [10]. Cardiac MIBG uptake is lower in PD patients with orthostatic hypotension (OH) than in PD patients without OH. Vasomotor and cardiac sympathetic dysfunction probably is the primary cause of OH in PD, although baroreceptor reflex failure may also have a minor contribution. Nevertheless, it is unclear whether vasomotor and cardiac sympathetic dysfunction in patients with PD is caused primarily by the impairment of preganglionic or postganglionic lesions [32]. The relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with PD were also assessed. 123I-MIBG uptake is lower in PD patients with VH than in PD patients without VH. Severe autonomic dysfunction in PD with VH is probably attributed to Lewy body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both [33, 34]. An association between olfactory dysfunction and cardiac MIBG uptake in patients with PD was investigated. There is a significant correlation between cardiac MIBG uptake and the cross-cultural smell identification (CCSI) score in patients with PD independent of the disease duration or clinical rating of motor status. Therefore, it is hypothesized that functional losses of the olfactory and cardiac sympathetic systems are closely coupled in PD [35]. At last, Miyamoto et al. reported markedly reduced cardiac MIBG uptake, consistent with the loss of sympathetic terminals, in idiopathic REM sleep behavior disorder (RBD). The authors also demonstrated that this reduction is of the same magnitude as that found in patients with PD. The results are consistent with the hypothesis that idiopathic RBD in older patients may represent a prodromal phase of neurodegenerative diseases such as LBD [36, 37].
Conclusions This review underlines the importance of targeting neuronal dysfunction with 123I-MIBG scintigraphy in patients with LBD, particularly in PD and DLB; indeed, this technique may contribute to early diagnosis and appropriate treatment in these patients.
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However, multicentre studies with large number of patients and an accurate follow-up period are necessary to confirm the role of this technique in LBD. Acknowledgments The authors are grateful to nuclear medicine technicians of Maggiore Hospital of Bologna for their technical support. Special thanks to Miss Barbara Muoio of the Catholic University of the Sacred Heart in Rome for her bibliographic support.
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