Fig. 21.1
[123I]-MIBG scintigraphy (planar imaging performed at 4 h after tracer injection) showing abnormal myocardial uptake in a patient with Parkinson’s disease (a) and in a patient with dementia with Lewy body (b), and normal myocardial uptake in a patient with multiple system atrophy (c) and in a patient with Alzheimer’s disease (d), demonstrating myocardial sympathetic impairment in patients with Lewy body disease (a, b) and normal myocardial sympathetic innervation in other neurodegenerative diseases (c, d)
21.2.2 [123I]-MIBG Scintigraphy in Parkinson’s Disease and Other Parkinsonisms
Hirayama et al. first reported a reduced myocardial uptake of [123I]-MIBG in PD patients compared to normal controls (Hirayama et al. 1995). Since then, multiple clinical studies were performed showing a significant reduction in myocardial [123I]-MIBG uptake in PD patients which reflected the presence of a myocardial sympathetic dysfunction in this neurodegenerative disease (Treglia et al. 2010, 2012).
[123I]-MIBG scintigraphy findings showed that myocardial postganglionic sympathetic dysfunction in patients with PD is already present in early disease without clinical evidence of autonomic dysfunction. Furthermore, [123I]-MIBG myocardial uptake was sometimes impaired in PD even in the absence of abnormal findings on autonomic testing, suggesting that [123I]-MIBG scintigraphy is more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction (Takatsu et al. 2000; Taki et al. 2000; Oka et al. 2006). However, some studies reported a relatively lower sensitivity of [123I]-MIBG scintigraphy in PD patients with early stage of disease compared to those with advanced stage (Orimo et al. 2012; Treglia et al. 2012).
Regarding the correlation between clinical subtypes of PD and myocardial [123I]-MIBG uptake, conflicting results are reported in the literature: in some studies a lower myocardial [123I]-MIBG uptake in the akinetic-rigid type of the disease compared to the tremor-dominant type was described (Spiegel et al. 2007; Chung et al. 2011), whereas in a recent article myocardial sympathetic innervation was found more severely impaired in the tremor-dominant type (Chiaravalloti et al. 2012).
All the major non-motor manifestations noted in PD have been reported to be associated with myocardial sympathetic denervation. These include olfactory dysfunction, REM sleep behavior disorder, dementia, visual hallucinations, and orthostatic hypotension, although literature on the latter has not been perfectly consistent (Kashihara et al. 2010; Kitayama et al. 2008; Lee et al. 2006; Miyamoto et al. 2006; Oka et al. 2007a, b; Suzuki et al. 2006; Treglia et al. 2010).
Regarding the correlation between genetic characteristics of PD and myocardial [123I]-MIBG uptake, myocardial sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. In particular, myocardial [123I]-MIBG 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 (Quattrone et al. 2008).
Another challenge is the presence of correlation between disease severity and myocardial uptake of [123I]-MIBG. Some studies found no correlation; on the other hand, other studies reported a significant correlation between myocardial [123I]-MIBG uptake and disease severity or duration, as reported by a recent systematic review (Treglia et al. 2012).
Another important issue to be clarified is the correlation between myocardial [123I]-MIBG uptake and the presence of autonomic dysfunction in PD. No clear data are available whether [123I]-MIBG uptake is associated with symptoms and signs of dysautonomia in PD patients. Some studies found no differences in myocardial [123I]-MIBG uptake in relation to the presence and severity of clinical autonomic dysfunction or abnormal autonomic tests (Braune et al. 1999; Berganzo et al. 2012). On the other hand, de novo PD patients without clinical evidence of autonomic dysfunction showed reduced myocardial [123I]-MIBG uptake suggesting that [123I]-MIBG scintigraphy could be a sensitive method to detect latent subclinical autonomic dysfunction (Courbon et al. 2003; Oka et al. 2006).
However, among PD patients, the severity of myocardial sympathetic denervation does not seem to be related to the severity of loss of nigrostriatal dopaminergic neurons. For these reasons, autonomic dysfunction, as measured by sympathetic noradrenergic denervation, seems to occur independently of the dopaminergic impairment that causes the movement disorders in PD. Because of this independence, evidence of myocardial sympathetic denervation can be an early finding but may also occur after the movement disorder is overt in PD (Treglia et al. 2014).
Sequential imaging using [123I]-MIBG scintigraphy revealed progressive degeneration of the cardiac sympathetic nerves in patients with PD (Watanabe et al. 2011). Therefore, [123I]-MIBG scintigraphy could be a useful tool in clinical trials that intend to prove neuroprotection among patients with PD.
In the clinical practice, [123I]-MIBG scintigraphy may help physicians for the differential diagnosis between PD and other parkinsonisms, in particular degenerative parkinsonisms such as MSA, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). This differential diagnosis may be difficult using other neuroimaging methods such as striatal dopaminergic imaging (Treglia et al. 2014).
By contrast to PD, in MSA the autonomic nervous system is mainly affected in its preganglionic structures, and most MSA patients present central catecholamine deficiency but preserved myocardial sympathetic innervation showing normal myocardial [123I]-MIBG uptake (Reinhardt et al. 2000; Braune et al. 1999). In PSP and CBD patients, myocardial sympathetic denervation is usually absent resulting in a normal myocardial [123I]-MIBG scintigraphy compared to PD patients; few data are recorded for other parkinsonisms (Treglia et al. 2012).
Some recent meta-analyses reported the diagnostic performance of myocardial [123I]-MIBG scintigraphy in the differential diagnosis between PD and other parkinsonisms (King et al. 2011; Orimo et al. 2012; Treglia et al. 2011, 2012). Although these meta-analyses showed differences in methodology, they confirmed the high sensitivity, specificity, and accuracy of [123I]-MIBG scintigraphy in differentiating PD from other parkinsonisms.
Nevertheless, possible causes of false-positive and false-negative results of this scintigraphic method should be kept in mind. It should be noted that various heart diseases and diabetes may damage the postganglionic sympathetic neurons, leading to a decreased myocardial [123I]-MIBG uptake and false-positive [123I]-MIBG scintigraphy findings (Treglia et al. 2012). In most of the published studies, patients who had heart diseases were excluded, but in clinical setting tomographic images obtained by using single-photon emission computed tomography (SPECT) might be useful for differentiating regional defects due to heart diseases from global denervation of DLB.
Furthermore, an appropriate selection of patients taking into account drugs that may influence myocardial [123I]-MIBG uptake (Solanki et al. 1992; Flotats et al. 2010) should be performed.
In comparison with PD, patients with other parkinsonisms usually show a higher myocardial [123I]-MIBG uptake. Nevertheless, myocardial [123I]-MIBG uptake in patients with other parkinsonisms (especially in patients with MSA and PSP) was often found slightly reduced in comparison to healthy controls, and this finding may cause false-positive results in some cases (Treglia et al. 2012). Mild degeneration of the myocardial sympathetic nervous system, as demonstrated in patients with MSA (Orimo et al. 2007b), may account for this scintigraphic finding.
False-positive results of [123I]-MIBG scintigraphy may be due also to age-related and not only LBD-related postganglionic sympathetic degeneration, because myocardial [123I]-MIBG uptake has significant age-related decrease (Sakata et al. 2009).
False-negative results of [123I]-MIBG scintigraphy in patients with PD may be caused by early stage of disease, disease duration less than 1 year, tremor-dominant phenotypes, and some genetically determined PD (Treglia et al. 2012).
21.2.3 [123I]-MIBG Scintigraphy in Dementia with Lewy Bodies and Other Dementias
Several single-center studies using [123I]-MIBG scintigraphy have demonstrated reduced myocardial MIBG uptake in DLB, as opposed to other dementias (Treglia et al. 2010).
Estorch et al. found that myocardial [123I]-MIBG uptake was significantly decreased in patients with DLB in comparison to all other neurodegenerative diseases with cognitive impairment with a sensitivity and a specificity of 94 and 96 %, respectively (Estorch et al. 2008). The same group found a high diagnostic performance of [123I]-MIBG scintigraphy also at early imaging (Camacho et al. 2013).
In probable DLB, an impairment of both myocardial [123I]-MIBG uptake and striatal dopaminergic imaging was found (Camacho et al. 2011; Treglia et al. 2014), suggesting that myocardial sympathetic degeneration and nigrostriatal degeneration parallel similarly in these patients.
A recent meta-analysis including eight studies found that the pooled sensitivity of [123I]-MIBG scintigraphy in detection of DLB was 98 % and the pooled specificity in differential diagnosis between DLB and other dementias was 94 % (Treglia and Cason 2012).
Also striatal dopaminergic imaging has demonstrated high diagnostic accuracy in differential diagnosis between DLB and other dementias (Papathanasiou et al. 2012). An advantage of myocardial [123I]-MIBG scintigraphy over other functional studies in differential diagnosis between DLB and other dementias is the short acquisition time and comfortable planar imaging, which is appreciated by patients and their caregivers (Estorch et al. 2008).
21.3 PET Tracers
[123I]-MIBG is not an optimal tracer for the assessment of sympathetic myocardial innervation. To a considerable extent it is taken up also in extraneuronal structures, i.e., myocardial myocytes. The specific uptake via the neuronal norepinephrine transporter accounts for only about 50 % of uptake. Furthermore, [123I]-MIBG does not allow exact quantification of myocardial innervation. PET offers higher sensitivity and more accurate measurements of tissue radioactivity concentrations than SPECT, allowing the quantification of myocardial innervation.
21.3.1 [11C]-mHED
[11C]-mHED is a metaraminol analog and it is a good substrate for the norepinephrine transporter. It shares the same neuronal uptake mechanism as norepinephrine and is also resistant to norepinephrine metabolism. By using [11C]-mHED, the myocardial retention fraction can be calculated based on kinetic modelling (Munch et al. 2000). Further advantages of [11C]-mHED in comparison with [123I]-MIBG are the higher specific radioactivity and the fact that this PET tracer is primarily taken up via specific uptake (about 92 %). [11C]-mHED not only provides quantitative measurements of myocardial tracer retention, reflecting sympathetic nerve density, but also allows for the detailed assessment of regional variations in left ventricular innervation (Bengel and Schwaiger 2004; Raffel and Wieland 2001; Raffel et al. 2006a, b).
Berding et al. performed a preliminary study supporting the concept that measurements of sympathetic myocardial innervation using [11C]-mHED PET may contribute to the differential diagnosis of parkinsonisms. They also suggested a role for quantitative innervation imaging, particularly at early stages of PD (Berding et al. 2003).
However, Raffel et al. showed that PET with [11C]-mHED detected significant losses of myocardial sympathetic nerve fibers not only in patients with PD but also in some patients with MSA and PSP. In all patients with PD and with reduced [11C]-mHED retention, sympathetic denervation consistently was found to occur throughout the entire left ventricle. Although some patients with MSA also had complete left ventricular denervation, patients with MSA and PSP had mainly focal regions of denervation. In light of these findings, the scintigraphic detection of myocardial sympathetic denervation alone by [11C]-mHED PET could not be used to differentiate PD from MSA and PSP. Myocardial sympathetic denervation studied by [11C]-mHED PET was found not to be correlated with striatal denervation, suggesting that the neurodegenerative processes in these tissues occur independently (Raffel et al. 2006a, b).
In a recent prospective study, Wong et al. by using [11C]-mHED PET in 27 PD patients demonstrated that myocardial sympathetic denervation in PD is extensive, with a segmental pattern that involves the proximal lateral left ventricular wall most severely, with relative sparing of the anterior and proximal septal walls (Wong et al. 2012).
21.3.2 [18F]-dopamine
Another PET tracer used to map the regional distribution of myocardial sympathetic neurons is [18F]-dopamine (Goldstein et al. 2000a, b), which is available at National Institute of Health of Bethesda (USA). This tracer is transported into sympathetic nerve ending by specific uptake then is rapidly converted to fluoronorepinephrine (FNE) by dopamine beta-hydroxylase in neuronal vesicles. Uptake of [18F]-dopamine into sympathetic nerve terminals, with conversion to and storage of FNE in vesicles, would lead to more intense radioactivity signals from sympathetically innervated tissues compared to non-innervated tissues.
It was previously reported that patients with PD and orthostatic hypotension have remarkably decreased left ventricular myocardial concentrations of [18F]-dopamine (Goldstein et al. 1997; Goldstein et al. 2000a, b). [18F]-dopamine PET also demonstrated a reduction of myocardial uptake not only in PD patients who have orthostatic hypotension but also in one half of patients with PD without orthostatic hypotension (Goldstein et al. 2002). These findings confirmed that myocardial sympathetic denervation does not cause the orthostatic hypotension and autonomic failure in PD.
[18F]-dopamine PET may be useful to study the progression of myocardial sympathetic denervation in patients with PD (Li et al. 2002). This method was also found able to differentiate PD from MSA (Goldstein et al. 2008), whereas other LBD such as PAF presented a marked myocardial sympathetic denervation similar to PD (Tipre and Goldstein 2005; Goldstein and Sewell 2009).
21.4 Comparison Between Myocardial and Brain Innervation Imaging
In LBD, progressive nigrostriatal denervation and degeneration in the peripheral autonomic nervous system are typical features.
Nigrostriatal dopaminergic system may be evaluated by using both SPECT and PET tracers. SPECT of the nigrostriatal dopaminergic system is widely used in patients with LBD. For example, imaging of dopamine transporter (DAT) binding with [123I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan (FP-CIT) successfully visualizes presynaptic dopaminergic degeneration of the nigrostriatal tract. This procedure allows differentiation of DLB from other dementias (Papathanasiou et al. 2012) and degenerative parkinsonism from movement disorders that are not associated with dopaminergic deficit, such as essential tremor (Treglia et al. 2014). DAT imaging alone, however, does not differentiate the various types of degenerative parkinsonism with sufficient accuracy (Südmeyer et al. 2011; Treglia et al. 2014).
In the latter regard, SPECT of dopamine D2 receptors with radioligands such as [123I]-(S)-2-hydroxy-3-iodo-6-methoxy-N-[1-ethyl-2-pyrrodinyl)-methyl]benzamide (IBZM) may be helpful, because patients with atypical parkinsonism usually display lower D2 receptor binding than do PD patients (Südmeyer et al. 2011).
The radiopharmaceutical 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine ([18F]-DOPA) is the most used PET tracer to evaluate the nigrostriatal dopaminergic system. [18F]-DOPA allows to evaluate the first step in dopaminergic transmission, namely, dopamine synthesis, which takes place in the presynaptic dopaminergic neurons. [18F]-DOPA is taken up into neurons by an active transport system and is converted to [18F]-dopamine by aromatic amino-acid decarboxylase (AADC), which represents the rate-limiting step for dopamine synthesis in dopaminergic neurons. As such, [18F]-DOPA uptake reflects the synthetic ability of dopaminergic neurons to produce dopamine through AADC. Striatal [18F]-DOPA PET findings are usually impaired in patients with neurodegenerative parkinsonisms (Berti et al. 2011).
Several studies in the literature compared myocardial sympathetic with striatal dopaminergic innervation imaging by using SPECT or PET tracers in LBD.
Spiegel et al. demonstrated that in early PD patients, binding of striatal FP-CIT correlated significantly with cardiac [123I]-MIBG uptake. FP-CIT SPECT and [123I]-MIBG scintigraphy could contribute to the early diagnosis of PD. In addition, the functional loss of nigrostriatal and cardiac sympathetic neurons seemed to be coupled closely (Spiegel et al. 2005).
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