Locus
Inheritance
Gene
Cardiac MIBG uptake
Lewy bodies
PARK1
AD
SNCA mutation
Reduced
+
PARK2
AR
Parkin
Normal
−
PARK4
AD
SNCA multiplication
Reduced
+
PARK6
AR
PINK1
Reduced or normal
+
PARK7
AR
DJ-1
Reduced or normal
Not published
PARK8
AD
LRRK2
Reduced or normal
+ or −
15.2 Gaucher Disease (GD)
Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase are associated with GD, the most common autosomal-recessive lysosomal storage disease. It is now clear that a subset of patients with GD develop parkinsonism. Postmortem brain tissue examination of patients with GD associated with parkinsonism has consistently shown classic PD pathology. Itokawa et al. [78] reported a patient with type I GD who had near-normal cardiac MIBG uptake, with partially defective cardiac MIBG uptake considered to be due to old myocardial infarction confirmed on Tc-99 m SPECT. On the other hand, Lebouvier et al. [79] reported a case with type I GD and abnormal cardiac MIBG uptake, with reduced early and delayed H/M ratios. Another study that sequenced the entire coding exons and exon/intron boundaries reported that 27 of 144 families (18.8 %) of index patients with Japanese familial PD were heterozygous for known GD mutations and presented with reduced cardiac MIBG uptake [80].
15.3 123I-MIBG Cardiac Scintigraphy Findings in Other Lewy Body Diseases
Cardiac sympathetic denervation has been reported to develop in patients with other Lewy body diseases, such as DLB and pure autonomic failure (PAF). In this regard, 123I-MIBG cardiac scintigraphy can be useful for differentiating Lewy body diseases from other parkinsonian syndromes and dementias. Furthermore, RBD is observed in α-synucleinopathy, especially in relation to Lewy body disease.
For this reason, we discuss PAF and RBD in this chapter, while DLB is described in Chap. 16.
15.3.1 Pure Autonomic Failure
15.3.2 Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD)
RBD is characterized by dream-enactment behavior resulting from muscle activity during REM sleep. The development of RBD may be one of the first manifestations of α-synucleinopathy including PD, DLB, and MSA. While the exact mechanism of RBD is still unclear, it is speculated that disturbances in regions of the brainstem that control REM sleep play a pathological role. A few studies reported significantly reduced cardiac MIBG uptake in patients with idiopathic RBD similar to PD with and without RBD [83, 84]. The results suggest that most of RBD indicate Lewy body diseases. Furthermore, Koyama et al. [85] reported the presence of hyposmia, impaired facial expression recognition, and reduced cardiac MIBG uptake in one RBD patient free of parkinsonism. Impaired facial expression recognition may reflect the dysfunction of the amygdala. In RBD patients, neurodegeneration may occur more diffusively than the brainstem alone.
15.4 123I-MIBG Cardiac Scintigraphy Findings in Other Neurodegenerative Parkinsonism and Related Disorders
The clinical feature of atypical neurodegenerative parkinsonism, such as MSA, PSP, and CBD, resembles those of PD, especially in the early stages. Despite the presence of clinical consensus criteria for PD and other parkinsonisms, accurate diagnosis of these disorders remains a challenge for neurologists. 123I-MIBG cardiac scintigraphy is a useful imaging tool for differentiating PD from other parkinsonisms.
15.4.1 Neurodegenerative Parkinsonism
15.4.1.1 Multiple System Atrophy
MSA is a late-onset neurodegenerative disease characterized by progressive autonomic failure, parkinsonism, and cerebellar and pyramidal tract symptoms. Neurodegeneration and the formation of glial cytoplasmic inclusions immunostained with α-synuclein are the hallmark of the disease. 123I-MIBG cardiac scintigraphy is significantly higher in MSA than PD or within the normal range [86]. However, cardiac MIBG uptake is not necessarily preserved in patients with MSA, and approximately 30 % of patients with MSA have reduced cardiac MIBG uptake, and these levels do not correlate with disease duration or severity [87]. The mean value of the H/M ratio in striatonigral degeneration (SND), a subtype of MSA, with OH is lower than SND without OH [86].
It is known that central or preganglionic lesions, such as those in the cardiovascular autonomic center of the ventrolateral medulla or intermediolateral cell column of the spinal cord, contribute to the dysautonomia of MSA. Cohen et al. [88] hypothesized that in MSA, preganglionic lesions cause dysfunction of the postganglionic sympathetic fibers through the transsynaptic effects. Postmortem examination of a MSA patient with a slightly reduced cardiac MIBG uptake demonstrated no obvious neuronal loss in the peripheral sympathetic ganglia. Furthermore, TH-immunoreactive epicardial nerve fibers in the anterior wall of the left ventricle of the heart were preserved in patients with MSA [5]. Based on the above findings, it was proposed that postganglionic sympathetic nerves are not involved in MSA; rather, the central and preganglionic lesions account for the slightly reduced cardiac MIBG uptake in MSA [5]. The same group also reported mild or moderate decrease in the number of TH-immunoreactive epicardial nerve fibers of six of 15 patients with MSA, of whom four showed a decrease in TH immunoreactivity in the neuronal somata in the sympathetic ganglia. These pathological changes supported the hypothesis that preganglionic lesions cause dysfunction of the postganglionic sympathetic fibers through the transsynaptic effects in MSA.
15.4.1.2 Progressive Supranuclear Palsy
PSP is characterized by parkinsonisms, gaze palsy, pseudobulbar palsy, dysarthria, axial rigidity, frontal lobe dysfunction, and dementia and thus partially resembles PD. However, the clinical spectrum of PSP is known to be wider than originally described. The typical pathology is abnormal tau deposition that affects neurons and glial cells represented by tufted astrocytes. The mean value of the H/M ratio in patients with PSP is significantly higher than in PD, but the majority of patients have normal to slightly reduced cardiac MIBG uptake compared with normal control subjects [3, 83, 86, 89, 90]. Orimo et al. [6] reported that TH-immunoreactive epicardial nerve fibers were well preserved in five pathologically confirmed patients with PSP.
15.4.1.3 Corticobasal Degeneration
CBD is characterized by asymmetric symptoms including rigidity and tremor, thus partially resembling PD. However, some patients with CBD present with clinical symptoms that do not resemble those of PD, such as dystonia, myoclonus, apraxia, cortical sensory deficits, and alien limb phenomena. In addition, some suffer from various cognitive and language deficits. CBD is pathologically characterized by abnormal tau deposition in neurons and glial cells, including astrocytic plaques. Only a few studies examined 123I-MIBG cardiac scintigraphy in patients with CBD. The H/M ratio of CBD is not different from that of normal control subjects [8, 89, 90].
Another case report of postmortem histopathological examination of a CBD patient demonstrated well-preserved TH-immunoreactive epicardial nerve fibers, similar to the control subjects [8].
15.4.2 123I-MIBG Cardiac Scintigraphy Findings in Other Related Disorders
15.4.2.1 Vascular Parkinsonism
Orimo et al. [21] examined 123I-MIBG cardiac scintigraphy in 11 patients with vascular parkinsonism and found it was not significantly different from normal and disease control subjects. Furthermore, the mean H/M ratio of the PD patients was significantly lower than patients with vascular parkinsonism. The same findings were confirmed in six patients [12] and 19 patients [91] with vascular parkinsonism.
15.4.2.2 Essential Tremor (ET)
ET is characterized by postural tremor affecting the hands, head, and other parts of the body. By definition, patients with ET should not have other clinical signs of parkinsonism. In some cases, it is difficult to differentiate ET from PD, especially in the early stages of the disease.
Orimo et al. [21] indicated that cardiac MIBG uptake measured in five patients with ET was comparable to that in normal and disease control subjects. Another group [92] also examined 123I-MIBG cardiac scintigraphy in 20 patients with ET and reported significantly higher mean H/M ratio in patients with ET than in TDT or early PD [rated at H-Y of I and II with recent diagnosis (symptom duration 2 years)]. However, the mean H/M ratio of the ET group was not significantly different from that of the control group. In the same study [92], the H/M ratio was higher in patients with ET than two standard deviations above the range of the ratio in patients with early PD or TDT. Another study of 16 patients with rest and postural tremor (mixed tremor), together with mild extrapyramidal features and abnormal striatal 123I-FP-CIT SPECT, reported reduced cardiac MIBG uptake in delayed images in half of the patients [93]. The results suggest that the combined use of both 123I-FP-CIT SPECT and 123I-MIBG cardiac scintigraphy in patients with mixed tremors and extrapyramidal features can help distinguish patients with ET from those with PD and parkinsonism.
15.4.2.3 Drug-Induced Parkinsonism
Drug-induced parkinsonism (DIP) is a heterogeneous clinical syndrome, but almost all patients with DIP have normal cardiac MIBG uptake. All patients show improvement or complete resolution of parkinsonism after withdrawal of the offending drug. However, some DIP patients with significantly reduced cardiac MIBG uptake develop persistent and worsening parkinsonism or PD after discontinuation of the offending drug. 123I-MIBG cardiac scintigraphy may be a useful tool for detecting DIP unrelated to PD and to identify DIP patients with subclinical PD [94–96] (Fig. 15.1).
Fig. 15.1
123I-MIBG cardiac scintigraphy in representative cases of Parkinson’s disease and related disorders. Cardiac MIBG uptake is lower than normal control in patients with Lewy body diseases such as PD, DLB, and PAF, but not in patients with other related disorders. (a) control, (b) vascular parkinsonism, (c) essential tremor, (d) Parkinson’s disease, (e) dementia with Lewy bodies, (f) pure autonomic failure, (g) multiple system atrophy-parkinsonism type, (h) progressive supra nuclear palsy, (i) corticobasal degeneration
15.4.2.4 Others
Spinocerebellar Ataxia Type 2
SCA2 is an autosomal-dominant neurodegenerative disorder associated with expanded CAG trinucleotide repeat in the ATXN2 gene. It is clinically characterized by gait and limb ataxia, dysarthria, supranuclear ophthalmoplegia, peripheral neuropathy, sleep disorders, postural tremor, chorea, myoclonus, parkinsonism, pyramidal signs, and dementia. Most cases exhibit the cerebellar phenotype, though few present with parkinsonism as the predominant phenotype instead of cerebellar ataxia. The levodopa-responsive parkinsonism is considered a rare clinical presentation in SCA2.
Koyano et al. [97] found reduced cardiac MIBG uptake in SCA2 parkinsonian phenotype with homozygous SCA2 expansion (36/38). Another group [98] reported the postmortem findings of a SCA2 patient with parkinsonian phenotype and reduced cardiac MIBG uptake. They found atrophy of the olivopontocerebellar system and substantia nigra. Both findings were compatible with SCA2. In addition, they also found Lewy body pathology in the SN, the locus coeruleus, dorsal motor nuclei of vagus, and cardiac sympathetic nerves. De Rosa et al. [99] performed 123I-MIBG cardiac scintigraphy in nine patients with SCA2 free of parkinsonism. The early and delayed H/M ratios were significantly lower in patients with SCA2 than the control subjects, though less marked than in PD patients. Another study reported the results of postmortem examination of a Japanese SCA2 patient with parkinsonism [100]. In addition to the classic SCA2 neuropathological changes, Lewy bodies and Lewy neurites were identified in brainstem nuclei. Furthermore, genetic analysis demonstrated the presence of shorter abnormal expansion of CAG repeats (less than 39). In comparison, the authors did not find Lewy body pathology in two SCA2 cases free of parkinsonism. The study provided neuropathological evidence for a correlation between Lewy body pathology and parkinsonism of SCA2.
Since 123I-MIBG cardiac scintigraphy demonstrated impairment of cardiac sympathetic function in SCA2, with and without parkinsonism, Lewy body pathology does not seem to explain all the findings of 123I-MIBG cardiac scintigraphy.
Machado-Joseph Disease (MJD)
MJD or SCA3 is an autosomal-dominant neurodegenerative disorder associated with expanded CAG trinucleotide repeat in ATXN3 gene. It is characterized by ataxia, ophthalmoplegia, peripheral neuropathy, pyramidal dysfunction, and movement disorders. Only a few MJD patients develop parkinsonism. Although MJD is a relatively rare disease, it is the most frequent spinocerebellar ataxia with a worldwide distribution.
In a study of 19 patients with MJD who underwent 123I-MIBG cardiac scintigraphy, the delayed H/M ratio was significantly lower in the patients than the control subjects, whereas the early H/M ratio was comparable between the two groups [101]. Six of the 19 patients showed abnormal sympathetic skin responses (SSR). The delayed H/M ratio was significantly lower in the latter group than in patients with normal SSR. These results suggest the presence of cardiac sympathetic dysfunction in MJD, as detected by 123I-MIBG cardiac scintigraphy, which appears to correlate with sudomotor sympathetic dysfunction.
15.5 123I-MIBG Cardiac Scintigraphy Findings in Comorbidities
Finally, we describe the comorbidities associated with reduced cardiac MIBG uptake for careful interpretation of 123I-MIBG cardiac scintigraphy findings.
15.5.1 Congestive Heart Failure (CHF), Cardiomyopathy, and Ischemic Heart Disease
Kline et al. [102] were the first investigators to use 123I-MIBG cardiac scintigraphy and explore its utility in quantitative measurement of myocardial catecholamine content. Activation of the sympathetic nervous system is one of the main pathophysiological abnormalities associated with heart failure. The H/M ratio correlates significantly with myocardial noradrenaline concentration and with left ventricular ejection fraction in patients with idiopathic dilated cardiomyopathy [103]. Reduced cardiac MIBG uptake and high washout, especially reduced delayed H/M ratio, have been described in CHF [104], and the extent of such reduction correlated with the severity of CHF and response of treatment, prognosis, and mortality.
The failing heart requires sympathetic stimulation to increase cardiac performance, but paradoxically shows depletion of noradrenaline [105]. Recent studies have suggested that it is due to decreased noradrenaline reuptake [104, 106] and synthesis [107]. In this regard, Kanazawa et al. [108] demonstrated neurotransmitter switching from predominantly catecholaminergic to cholinergic or cholinergic transdifferentiation of the cardiac sympathetic nervous system in patients with CHF, as an adaptive response. These results may explain the reduced cardiac MIBG uptake in patients with CHF.
With regard to ischemic heart disease, cardiac MIBG washout is globally increased after myocardial infarction within 14 days of early reperfusion therapy, even in patients with preserved left ventricular function [109]. Podio et al. [110] reported no changes in cardiac MIBG uptake from 1 week after infarction to after 30 months of follow-up. Enhanced washout may reflect increased sympathetic nerve tone and represent increased catecholamine turnover or impaired reuptake in the subacute phase of myocardial infarction [109].
15.5.2 Diabetes Mellitus (DM)
Evaluation of cardiac MIBG uptake in patients with DM began in 1988. The first report of use of 123I-MIBG cardiac scintigraphy was in patients with diabetic autonomic neuropathy with sudden cardiac death presumably due to QTc interval prolongation [111], though the usefulness of imaging of the sympathetic nervous system in DM is unclear [112]. One study that followed 144 patients with DM and no other cardiac disease for 7 years after 123I-MIBG cardiac scintigraphy showed that reduced cardiac MIBG uptake was associated with increased risk of cardiac mortality [113]. Coronary arterial and arteriolar narrowing is common in patients with diabetic autonomic neuropathy; therefore, reduced cardiac MIBG uptake may reflect a combination of denervation and decreased delivery of the trace to the sympathetic nerves due to coronary hypoperfusion [114]. However, reduced cardiac MIBG uptake can also occur in patients with DM without any evidence of coronary heart disease or autonomic neuropathy [115]. In addition, enhanced washout rate is independently associated with the incidence of major adverse cardiac and cerebrovascular events in type 2 diabetic patients free of structural heart disease [116].
Experimental studies in a rat model of DM showed a high cardiac MIBG washout rate, but unlike patients with heart failure. This was not due to systemic sympathetic hyperactivity. Rather, it was likely due to dysfunction of the reuptake and/or pooling mechanism since the plasma and myocardial noradrenaline concentrations in diabetic rats were significantly lower than those in nondiabetic rats [117].
Cardiac MIBG uptake is comparatively preserved in diabetic patients without heart failure [118] or even improved when blood sugar level is under control [119]. Thus, the presence of DM alone does not always cause reduced cardiac MIBG uptake. Recently Slaets et al. [120] described no significant difference in H/M ratio among DLB patients with DM, arterial hypertension, hyperlipidemia, ischemic heart disease, heart failure, and pharmacological treatment and those without clinically observable conditions. Furthermore, Otsuka et al. [121] examined differences in H/M ratio in patients with Alzheimer disease (AD) or amnestic MCI (aMCI) with or without DM. In their study, 123I-MIBG cardiac scintigraphy was performed in both the AD or aMCI without DM (AD/DM(−), n = 248) and AD or aMCI with DM (AD/DM(+), n = 46) and in age-matched control subjects (C, n = 28). The early/delayed H/M ratios in AD/DM(−), AD/DM(+), and C were 2.39 ± 0.38/2.37 ± 0.44, 2.37 ± 0.3/2.31 ± 0.34, and 2.43 ± 0.24/2.44 ± 0.26, respectively, with no significant difference among the three groups. Five of 46 patients of the (AD/DM(+)) group showed slightly low H/M ratios but none of these patients showed no accumulation of MIBG in the planar image as typically seen in PD patients. These results suggest that DM does not always have a significant effect on cardiac MIBG uptake, particularly DM without diabetic autonomic neuropathy. Further studies are needed to confirm the cardiac MIBG uptake in DM patients with or without autonomic neuropathy.
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