The PARK1 clinical phenotype is characterized by severe parkinsonism with dementia and sleep disturbances [27]. Neuropathological examinations have revealed extensive Lewy bodies and Lewy neurites in the cortical and subcortical structures [28]. Tijero et al. previously reported that one asymptomatic carrier of the E41K mutation of α-synuclein showed markedly reduced cardiac MIBG uptake [29]. Subsequently, they performed cardiac MIBG scintigraphy in six patients with PARK1, four of whom were symptomatic (ages: 28, 46, 52, and 59 years old) and two who were asymptomatic carriers (ages: 29 and 52 years old). The four symptomatic carriers and the older asymptomatic carrier had markedly reduced cardiac MIBG uptake. There was a complete absence of TH-immunoreactive nerve fibers in the epicardial nerve fascicles from the two autopsied patients [30].

Orimo et al. described the first three cases of pathologically confirmed familial PD with a parkin mutation [31]. Patient 1 was a 73-year-old man with a homozygous exon 4 deletion in the parkin gene. Cardiac MIBG uptake at the age of 70 (46 years after onset) was normal, both in the early and the delayed phase. Postmortem examination revealed the loss of pigmented neurons and gliosis in the substantia nigra pars compacta and locus coeruleus, with no Lewy body pathology. Patient 2 was a 66-year-old man with a homozygous exon 4 deletion in the parkin gene. Cardiac MIBG uptake at the age of 63 years (35 years after onset) was normal in the early phase and slightly reduced in the delayed phase. Postmortem examination revealed a loss of pigmented neurons and gliosis in the substantia nigra pars compacta and locus coeruleus, with no Lewy body pathology. The weight of the heart was 400 g and a histological examination was unremarkable. Patient 3 was a 70-year-old man with a homozygous exon 4 deletion in the parkin gene. He had been previously described clinically and neuropathologically [32]. Postmortem examination revealed a loss of pigmented neurons and gliosis in the substantia nigra pars compacta and locus coeruleus, with no Lewy pathology. Cardiac tissues from the three patients were immunohistochemically examined using an antibody against TH to determine whether the cardiac sympathetic nerve was pathologically involved. Postmortem examination revealed that TH-immunoreactive nerve fibers in the epicardial nerve fascicles were well preserved in all three patients. This study confirmed that the cardiac sympathetic nerve is well preserved in PARK2 with a homozygous exon deletion, which accounts for the normal cardiac MIBG uptake. Moreover, normal cardiac MIBG uptake may have potential diagnostic value to indicate the absence of Lewy body pathology, even in patients with levodopa-responsive parkinsonism, such as in parkin disease.

Familial PD linked to the multiplication of α–synuclein is autosomal dominant and is characterized by an early onset age, autonomic disturbance, and rapidly progressive dopa-responsive parkinsonism, followed by dementia [33]. Reduced cardiac MIBG uptake or fluorodopamine uptake on positron emission tomography has been reported in patients with α–synuclein multiplication [34, 35]. Cardiac tissues from three patients with PD linked to α–synuclein duplication were immunohistochemically examined to determine whether the cardiac sympathetic nerve was pathologically involved [36]. The proband (patient 1) developed parkinsonism at the age of 61 and died at the age of 70. Her uncle (patient 2), who was also her husband, developed parkinsonism at the age of 71 and died at the age of 78. Their elder son (patient 3) developed parkinsonism at the age of 39 and died at the age of 54. The clinical and neuropathological findings of these patients have been reported elsewhere [37]. Quantitative PCR analysis demonstrated that all the patients were heterozygous for an α–synuclein duplication [38]. In each of the three patients, sections from the anterior wall of the left ventricle and the paravertebral sympathetic ganglia were immunostained with antibodies against TH, NF, or phosphorylated α-synuclein. TH-immunoreactive nerve fibers were markedly decreased and NF-immunoreactive nerve fibers were moderately decreased, with sparse α-synuclein aggregates, in the epicardial nerve fascicles from all three patients [36]. This study indicates that degeneration of the cardiac sympathetic nerve occurs in PD linked to α–synuclein duplication, accounting for the reduced cardiac MIBG or fluorodopamine uptake. Moreover, it further supports our previous conclusion that the degeneration of the cardiac sympathetic nerve is closely related to the presence of Lewy bodies.

PD associated with LRRK2 mutations is an autosomal dominant form of familial PD and is characterized by middle to late onset as well as dopa-responsive parkinsonism similar to sporadic PD. Dementia is not common [39]. Neuropathological findings are mostly inconsistent, showing both Lewy pathology (and sometimes tau- and ubiquitin-containing inclusions) and pure nigral degeneration without Lewy bodies, with or without neurofibrillary tangles [40]. In patients with PD associated with a LRRK2 mutation, such as the Sagamihara family [41] with I2020T LRRK2 mutation, cardiac MIBG uptake was normal to slightly reduced in most patients in this family [42]. Cardiac fluorodopamine uptake was reduced in a patient with PD linked to G2019S LRRK2 mutation [43]. Cardiac tissues from four patients with PD associated with LRRK2 mutation were immunohistochemically examined to determine whether the cardiac sympathetic nerve was pathologically involved. The clinical and pathological findings of the three patients have been previously reported [40–42]. In one of the three patients, Lewy body pathology was found in the central nervous system but was absent in the other two patients. The fourth patient was a 68-year-old woman. At the age of 51, she developed a gait disturbance and was diagnosed with PD. These features responded well to levodopa. She developed “wearing-off” motor fluctuations since the age of 57 and visual hallucination at the age of 64. At the age of 68, she died of pneumonia. Cognitive impairments and autonomic dysfunctions were not found. The fourth patient was genetically determined to have an I2020T amino acid substitution in LRRK2. Cardiac MIBG uptake at the age of 66 (in Hoehn and Yahr stage 5) was normal in the early phase and slightly reduced in the delayed phase. Macroscopic examinations of the brain revealed a marked depigmentation in the substantia nigra, where marked neuronal loss and gliosis with extraneuronal melanin were observed. These changes were prominent in the substantia nigra pars reticulata. In the locus coeruleus, only mild gliosis was observed and the dorsal motor nucleus of the vagus was almost normal. No Lewy bodies and Lewy neurites were found in any brain lesions using hematoxylin and eosin and phosphorylated α-synuclein immunostaining. In three of four patients who had no Lewy bodies and Lewy neurites, the cardiac sympathetic nerves were well preserved. In one patient who had Lewy bodies in the brain, the cardiac sympathetic nerve was markedly reduced, and a small number of α-synuclein aggregates in the epicardial nerve fascicles were observed. The present study indicates that degeneration of the cardiac sympathetic nerve is closely related to the presence of Lewy bodies in the central nervous system in PD associated with LRRK2 mutations in the Sagamihara family.