Takeshi Amino

Profound Cardiac Sympathetic Denervation Occurs in Parkinson Disease

In the last few years, cardiac sympathetic dysfunction in Parkinson disease (PD) has been postulated on the basis of decreased cardiac uptake of sympathoneural imaging tracers. However, the pathological substrate for the dysfunction remains to be established. We examined the left ventricular anterior wall from postmortem specimens with immunohistochemical staining for tyrosine hydroxylase (TH), neurofilament (NF) and S‐100 protein in PD patients and control subjects, and quantified the immunoreactive areas. As TH‐immunoreactive axons nearly disappeared and NF‐immunoreactive axons drastically decreased in number, the morphological degeneration of the cardiac sympathetic nerves in PD was confirmed. Quantitative analysis showed that sympathetic nerves were preferentially involved. Triple immunofluorolabeling for NF, TH, and myelin basic protein showed clearly the profound involvement of sympathetic axons in PD. The extent of involvement of the cardiac sympathetic nerves seems likely to be equivalent to that in the central nervous system, including the nigrostriatal dopaminergic system. PD affects the cardiac sympathetic nervous system profoundly as well as nigrostriatal dopaminergic system.

Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2

We performed [123I] MIBG myocardial scintigraphy in two of three patients with PARK2 from unrelated families and examined the heart tissues from the three patients immunohistochemically using an antibody against tyrosine hydroxylase (TH) to see whether cardiac sympathetic nerve is involved. Cardiac uptake of MIBG was normal except for a slight decrease in the late phase in one of the patients. Postmortem examination revealed that TH‐immunoreactive nerve fibers in the epicardium were well preserved in all three patients. The present study confirmed that cardiac sympathetic nerve is well preserved in PARK2 with a homozygous exon deletion, which accounts for normal cardiac uptake of MIBG. Moreover, normal cardiac uptake of MIBG might be of potential diagnostic value to indicate the absence of Lewy body pathology, even in patients with levodopa‐responsive Parkinsonism, as in PARK2.

16q-linked autosomal dominant cerebellar ataxia: A clinical and genetic study

The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

AbstractThe 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA; Online Mendelian Inheritance in Man [OMIN] #117210) is one of the most common ADCAs in Japan. Previously, we had reported that the patients share a common haplotype by founder effect and that a C-to-T substitution (−16C>T) in the puratrophin-1 gene was strongly associated with the disease. However, recently, an exceptional patient without the substitution was reported, indicating that a true pathogenic mutation might be present elsewhere. In this study, we clarified the disease locus more definitely by the haplotype analysis of families showing pure cerebellar ataxia. In addition to microsatellite markers, the single nucleotide polymorphisms (SNPs) that we identified on the disease chromosome were examined to confirm the borders of the disease locus. The analysis of 64 families with the −16C>T substitution in the puratrophin-1 gene revealed one family showing an ancestral recombination event between SNP04 and SNP05 on the disease chromosome. The analysis of 22 families without identifiable genetic mutations revealed another family carrying the common haplotype centromeric to the puratrophin-1 gene, but lacking the −16C>T substitution in this gene. We concluded that the disease locus of 16q-ADCA was definitely confined to a 900-kb genomic region between the SNP04 and the −16C>T substitution in the puratrophin-1 gene in 16q22.1.

Myocardial nerve fibers are preserved in MPTP-treated mice, despite cardiac sympathetic dysfunction

Recently, we reported a profound depletion of cardiac sympathetic nerve fibers in Parkinsons disease (PD). This cardiac sympathetic denervation is a characteristic hallmark of PD. Cardiac sympathetic dysfunction was also observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP)-treated mice, a model of PD. Although binding assay showed a decreased density of norepinephrine transporter (NET) in the hearts of the mice, their histopathological alterations have not been demonstrated. In this study, we investigated hearts of MPTP-treated mice with immunohistochemical method and Western blot analyses. MPTP-treated mice showed significant decreases in the contents of cardiac noradrenaline and dopamine, suggesting the sympathetic dysfunction. Synaptophysin-, tyrosine hydroxylase- or NET-immunoreactive nerve fibers were abundant in the hearts of control mice and MPTP-treated mice, without apparent differences between the two groups. Western blot analyses also showed no difference in the amounts of these proteins. Myocardial nerve fibers were well preserved in MPTP-treated mice, despite apparent cardiac sympathetic dysfunction.

Serum amyloid A level is increased in neuromyelitis optica and atypical multiple sclerosis with smaller T2 lesion volume in brain MRI

Serum amyloid A (SAA) is known to promote the development of T helper 17 cells (Th17) and can be a critical mediator of disease pathogenesis. We analyzed SAA levels in 40 patients with multiple sclerosis (MS) and related disorders, and 10 with non-inflammatory neurological disease (NIND) as controls. We found that SAA levels were significantly increased in neuromyelitis optica (NMO) patients and relapsing and remitting MS (RRMS) patients showing atypical phenotype with spinal cord lesions and smaller T2 lesion volume in brain MRI, resembling NMO. Therefore, SAA levels can be associated with clinical phenotypes in MS and NMO.

Decreased cardiac uptake of MIBG is a potential biomarker for the presence of Lewy bodies

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) has been reported in patients with Parkinsons disease (PD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). This imaging approach is a sensitive diagnostic tool that possibly differentiates PD and DLB from other movement disorders and Alzheimers disease (AD). We recently reported cardiac sympathetic denervation in PD, DLB and PAF, which accounts for the decreased cardiac uptake of MIBG in these disorders. Patients with PD, DLB and PAF have Lewy bodies (LBs) in the nervous system, whereas patients with multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration, AD and parkin-associated PD have no LBs in the nervous system. Even in patients with MSA, cardiac sympathetic denervation was associated with the presence of LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. Taken together, we conclude that the decreased cardiac uptake of MIBG is a potential biomarker for the presence of LBs.We infer that MIBG myocardial scintigraphy is a non-invasive tool that allows us to detect LBs during life.

Direct and accurate measurement of CAG repeat configuration in the ataxin-1 (ATXN-1) gene by “dual-fluorescence labeled PCR-restriction fragment length analysis”

AbstractSpinocerebellar ataxia type 1 (SCA1; OMIM: #164400) is an autosomal dominant cerebellar ataxia caused by an expansion of CAG repeat, which encodes polyglutamine, in the ataxin-1 (ATXN1) gene. Length of polyglutamine in the ATXN1 protein is the critical determinant of pathogenesis of this disease. Molecular diagnosis of SCA1 is usually undertaken by assessing the length of CAG repeat configuration using primers spanning this configuration. However, this conventional method may potentially lead to misdiagnosis in assessing polyglutamine-encoding CAG repeat length, since CAT interruptions may be present within the CAG repeat configuration, not only in normal controls but also in neurologically symptomatic subjects. We developed a new method for assessing actual CAG repeat numbers not interrupted by CAT sequences. Polymerase chain reaction using a primer pair labeled with two different fluorescences followed by restriction enzyme digestion with SfaNI which recognizes the sequence “GCATC(N)5”, lengths of actual CAG repeats that encode polyglutamine were directly detected. We named this method “dual fluorescence labeled PCR-restriction fragment length analysis”. We found that numbers of actual CAG repeat encoding polyglutamine do not overlap between our cohorts of normal chromosomes (n = 385) and SCA1 chromosomes (n = 5). We conclude that the present method is a useful way for molecular diagnosis of SCA1.

Taste impairment in Miller Fisher syndrome

Miller Fisher syndrome (MFS) was first described by Charles Miller Fisher in 1956 [1]; its cardinal clinical features are external ophthalmoplegia, ataxia, and areflexia. Taste impairment is considered to be an extremely rare clinical feature of MFS [2]. Here, we report a case of MFS with taste impairment and review the previously reported similar cases. A 53-year-old male was referred to our department because of taste impairment, diplopia, and gait disturbance. About 1 month before these symptoms emerged, he had experienced symptoms of an upper respiratory infection which spontaneously resolved. On admission, he was fully alert, his body temperature was 36.5 C and his blood pressure was 171/113 mmHg. He complained of diplopia, but neurological examination did not reveal obvious ocular movement abnormalities. He also complained of dysesthesia around his mouth and taste impairment, but did not have facial nerve palsy. He did not recognize sourness well, especially on his palate. He did not complain of lacrimal hyposecretion. He had no weakness in his extremities, but deep tendon reflexes were absent. He had ataxia in his extremities and trunk, and performed tandem gait with difficulty. Immunoglobulin (Ig) G anti-GQ1b antibodies were detected in the patient’s serum. Cerebrospinal fluid examination revealed a mild elevation of protein without pleocytosis: cell 1.3/ll, protein 50.2 mg/ dl, glucose 59 mg/dl, and oligoclonal bands were present. Brain magnetic resonance imaging operated on days 2 and 5 after disease onset revealed no abnormalities which could explain his neurological symptoms. Nerve conduction studies of his upper and lower extremities were normal. Electrogustometry revealed elevated thresholds in his right and left soft palates, but normal thresholds in the anterior two-thirds and posterior one-third of his tongue, suggesting dysfunction of the bilateral greater petrosal nerves. Four days after admission, neurological examination revealed obvious ocular movement abnormalities, impairment of abduction, adduction and supraduction of both eyes, resulting in a diagnosis of MFS. Intravenous immunoglobulin (0.4 g/kg/day) was immediately administered and his symptoms, including taste impairment, gradually improved. On day 35 after disease onset, electrogustometry revealed normal thresholds in his right and left soft palates. The frequency of taste impairment in patients with Guillain–Barré syndrome has been reported to be 0.6–2 % [3, 4]. Since only two other cases with MFS presenting with taste impairment have been reported in the literature [2, 5], taste impairment is a very rare clinical feature of MFS. Clinical features of these two patients and the present case are summarized in Table 1. Taste impairment in MFS could independently occur without facial nerve palsy and could be an initial symptom of MFS. Uchibori et al. [2] postulated that the presence of specific antibodies, including anti-GQ1b antibodies, might affect peripheral nerves associated with taste and taste buds in MFS patients with taste impairment. Since taste disturbance emerged without facial nerve palsy, a similar mechanism might be associated with the symptom in the present case. Because a continuous spectrum was suggested to exist between MFS Y. Yagi (&) H. Yokote Y. Watanabe T. Amino T. Kamata Department of Neurology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino, Tokyo 180-8610, Japan e-mail: yyagi-tmd@umin.ac.jp

Cervical dystonia in an Alzheimer's disease patient treated with donepezil.

The cholinesterase inhibitor donepezil is a safe, effective, and widely used drug for the long-term symptomatic treatment of Alzheimer’s disease (AD) [1]. Dystonia is a rare complication of donepezil treatment, and some authors have reported dystonia, including Pisa syndrome, in patients treated with this drug [2]. Here, we report an AD patient treated with donepezil who developed cervical dystonia. A woman in her late 70s was referred to our department because of progressive forgetfulness. She had impaired episodic memory for recent events and her mini-mental state examination score was 12. Eye movement was normal, and she did not have akinesia or rigidity in her extremities that would suggest parkinsonism. Brain magnetic resonance imaging showed mild brain atrophy, and 99mTc-ECD single-photon emission computed tomography showed diminished blood flow in both temporal and parietal lobes, but this was more severe in the left hemisphere. She was diagnosed with AD and was started on a 5-mg dose of donepezil. Within 1 month of beginning the donepezil regimen, she developed severe torticollis and complained of difficulty in walking and eating. Physical examination revealed no abnormality other than torticollis to the left side. Physical examination and imaging studies did not provide any evidence of Parkinson’s disease or dementia with Lewy bodies, and she did not take other dopaminergic or psychotropic drugs. Therefore, we suspected that her torticollis was a side effect of donepezil. Treatment with memantine did not affect her torticollis, and we decided to discontinue donepezil treatment. Several weeks later, she experienced relief of her torticollis. She was then treated with memantine alone and had a good outcome. Dystonia is considered a rare complication of treatment with donepezil, and previous case reports and the present findings provide evidence that this complication can be due to drugs that act on the cholinergic system. Kwak et al. [2] previously reported Pisa syndrome in an AD patient treated with donepezil, and Huvent-Grelle et al. [3] reviewed Pisa syndrome in AD patients treated with 3 cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. Villarejo et al. [4] suggested that cholinergic excess may induce Pisa syndrome. Although dystonia is a rare complication of cholinesterase inhibitors, clinicians must be aware of this phenomenon because of the increasing number of dementia patients and the growing use of cholinesterase inhibitors to treat them. Because cholinergic excess induced by cholinesterase inhibitors seems to be a cause of dystonia, treatment with the noncompetitive N-methyl-D-aspartate receptor antagonist memantine [5] is an alternative for AD patients who experience side effects on cholinesterase inhibitors.