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Freezing of gait (FOG) is one of the typical locomotion disorders associated with Parkinsonism, and is described as the inability to move the feet despite an attempt to walk. The fear of falling over and other symptoms of FOG can be distressing to patients. Considering conventional external cues and physical therapy, it is necessary for Parkinsonism patients suffering from FOG to swing the body laterally and rhythmically. The purpose of this study is to develop a wearable system that can assist rhythmical and lateral swing, and to validate the performance of the system in preventing FOG by conducting a gait experiment on a Parkinsonism patient. To develop this system, we simulated lateral swing in the standing position based on features of Parkinsonism and defined a mechanism and appropriate force configurations for the system. A power unit at the back of the waist transmits a cyclic force to the chest through a link in the frontal plane. A gait experiment was performed on a Parkinsonism patient with FOG to confirm the reduction in duration time and number of steps of turning. The result showed that the cyclic assistance of the system and gait cycle were harmonized, and the developed system decreased duration time and number of steps during turning by half. In addition, Pre-FOG, i.e., transient small stepping gait, occurred when turning without using the system, while it did not occur during and immediately after the use of the system. These results suggest that the developed system is effective in preventing occurrences of FOG by providing lateral and cyclic force to the upper body.

Background Mutations in the microtubule associated protein tau ( MAPT ) and progranulin ( PGRN ) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Recently, C9orf72 repeat expansion was reported to cause FTLD and amyotrophic lateral sclerosis (ALS). To date, no comprehensive analyses of mutations in these three genes have been performed in Asian populations. The aim of this study was to investigate the genetic and clinical features of Japanese patients with MAPT , PGRN , or C9orf72 mutations. Methods MAPT and PGRN were analyzed by direct sequencing and gene dosage assays, and C9orf72 repeat expansion was analyzed by repeat-primed PCR in 75 (48 familial, 27 sporadic) Japanese patients with FTLD, PSP, or CBS. Results We found four MAPT mutations in six families, one novel PGRN deletion/insertion, and no repeat expansion in C9orf72 . Intriguingly, we identified a de novo MAPT p.S285R mutation. All six patients with early-onset PSP and the abnormal eye movements that are not typical of sporadic PSP had MAPT mutations. The gene dosages of MAPT and PGRN were normal. Discussion MAPT p.S285R is the first reported de novo mutation in a sporadic adult-onset patient. MAPT mutation analysis is recommended in both familial and sporadic patients, especially in early-onset PSP patients with these abnormal eye movements. Although PGRN and C9orf72 mutations were rare in this study, the PGRN mutation was found in this Asian FTLD. These genes should be studied further to improve the clinicogenetic diagnoses of FTLD, PSP, and CBS.

SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real-time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG-PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age-associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment.

Among the motor tetrad of Parkinson's disease, akinesia is not easy to define and controversies still exist on the nature of akinesia. In 1972 Barbeau first described pure akinesia without rigidity or tremor responsive to L-dopa therapy, that is, akinesia due to striatal dopamine deficiency. Since 1974, Imai and Narabayashi have described a different type of pure akinesia, unresponsive to L-dopa treatment. This new condition exhibits only the freezing symptom, which is a breakdown of repetitive voluntary movements emerging through festination or suddenly, e.g., freezing of gait, micrographia and inaudible speech. Kinésie paradoxale is always accompanied by this type of akinesia. The author suggested that the main pathological structure of the condition was different from the nigrostriatal dopaminergic system and that the condition was different from Parkinson's disease. Subsequently we expanded our experience to more than 30 patients. All patients were sporadic and slowly progressive, and some had been followed for more than 10 years, still without rigidity or tremor. Slowly progressive supranuclear opthalmoplegia appeared later in several patients, in which progressive supranuclear palsy (PSP) was strongly suggested. Autopsy cases associated with this condition have been reported and pathologically revealed PSP. The nosological position and responsible lesion sites of this condition are discussed.

We report a 67-year-old female with orthostatic and voice tremor. Her orthostatic tremor mainly affected her lower extremities, alternating between antagonist muscle groups at a frequency of 4.4-4.8 Hz. The voice tremor ranged between 4.8 and 8.8 Hz. In this case, the frequency of voice tremor was same as that of orthostatic tremor, suggesting a common origin from a tremor-generating mechanism. These tremors were diagnosed as 'forme fruste' of the essential tremor, not the incipient stage of Parkinson's disease. Medications including clonazepam, perphenazine, Dopa and trihexyphenidyl hydrochloride had no effect on both the orthostatic and voice tremors, but propranolol was somewhat beneficial on voice tremor.

The mechanism of abnormal iron accumulation in the substantia nigra (SN) pars compacta of patients with Parkinson's disease (PD) is unknown. To explore this question, we made a hemiparkinsonism model in monkeys by injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the caudate or putamen on one side, and compared iron content in the SN and other basal ganglia structures by histochemistry. The injected side, especially the SN pars compacta, showed a marked increase in iron staining. Our study indicates that an injury to the nigrostriatal system by MPTP injection can induce iron accumulation in the SN.

Iron is increased in the substantia nigra of patients with Parkinson's disease, but the mechanism of its accumulation is unknown. We report the distribution of ferritin in the basal ganglia of hemiparkinsonian monkeys made by MPTP. We stereotactically injected MPTP unilaterally into the caudate nucleus of four monkeys, and the substantia nigra and the basal ganglia regions were stained for L-ferritin by an immunohistochemical method. The ferritin immuno-staining was most intense in the pallidum and the pars reticulata of the substantia nigra on both injected and non-injected sides. No significant difference was noted in the immunostaining for ferritin in the pars compacta of the substantia nigra between the injected and the non-injected side. Iron was increased in the pars compacta of the substantia nigra of this hemiparkinsonian monkeys in our previous study. Normal ferritin immunostaining on the injected side would indicate that iron accumulation is not related to altered metabolism of L-ferritin in this model.

Iron is increased in the substantia nigra of patients with Parkinson’s disease (PD). The mechanism of its accumulation, however, remains to be explored. In this study, we stereotactically injected MPTP into the unilateral putamen or caudate nucleus of six monkeys. The substantia nigra and the basal ganglia regions were stained for iron and ferritin by histochemical methods. We found a marked increase in the intensity of iron staining in the pars compacta of the substantia nigra. On the other hand, no significant difference was noted between the injected side and the non-injected side in ferritin steining. Such results suggest that the iron accumulation in this model as well as in PD may be a result of nigral degeneration, but unbalanced increase in iron with respect to the amount of ferritin may contribute to the progression of the disease by inducing oxidative stress.

Since 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found to produce symptoms similar to Parkinson’s disease (Langston et al., 1983), toxins with structure similar to MPTP have been hypothesized to result in cell death of mesencephalic dopamine neurons. 1,2,3,4-Tetrahydroisoquinoline (TIQ) has a structure similar to MPTP, and it, and its derivatives exist as endogenous amines in human brain (Ohta et al., 1987; Niwa et al., 1987; Niwa et al., 1989). Toxic properties of TIQ on mitochondria are similar to those of MPP+ (the oxidative product of MPTP) (Suzuki et al., 1988). N-methyltetrahydroisoquinoline (NMTIQ) is formed from TIQ by N-methyltransferase (Naoi et al., 1989a). NMTIQ is oxidized by both type A and B monoamine oxidases, and the N-methylisoquinolinium ion (NMIQ+), the oxidative product, inhibits activities of enzymes related to catecholamine metabolism (Naoi et al., 1989b). NMTIQ and NMIQ+ inhibits complex I activity, similarly to TIQ, and this inhibitory potency of NMIQ+ on complex I activity is stronger than that of MPP+ (Suzuki et al., 1992). Recently, we administered TIQ and its derivatives (NMTIQ and NMIQ+) to monkeys and observed mesencephalic dopamine neurons immunohistochemically. Using light and electron microscopy we found that NMTIQ produces changes in mesencephalic dopamine neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits selective destruction of nigrostriatal dopamine neurons in human and non-human primates along with clinical symptoms of Parkinson’s disease (Langston et al., 1983; Burns et al., 1983). Systemically administered MPTP is biotransformed into 1-methyl-4-phenylpyridium ion (MPP+), which then enters dopaminergic neurons via the dopamine uptake system to destroy nigral cells.

We studied the oxidation of sparteine in 36 patients with early onset (onset of age 1.5). These findings indicate that the oxidative capacity of sparteine is not defective but reduced in some patients with an earlier onset of Parkinson’s disease, possibly implying that the decreased activity of cytochrome P-450 responsible for the oxidation of sparteine would be a factor to accelerate the onset of the Parkinson’s disease.

Autopsy was performed on a 52 year old man with a 20-year history of neurological symptoms. At autopsy, both a brain stem tumor and a spinal cord tumor were found. These showed the features of pilocytic astrocytoma histologically. A pilocytic astrocytoma was also found in the optic chiasm upon microscopical examination. These three tumors were thought to be multicentric astrocytomas, because there was no continuity among them and no evidence of dissemination or metastasis by any pathway. From a review of the literature, the present case is considered to be an exceedingly rare one because of the multicentric sites of occurrence. Acta Pathol Jpn 39: 664 669, 1989.

Systemically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is biotransformed into 1-methyl-4-phenylpyridinium ion (MPP + ), which enters dopaminergic neurons via the dopamine uptake system to destroy nigral cells. Either MPP + is retrogradely transported to the cell body after being taken up at the nerve terminals, or the dopamine uptake sites on the cell body and its dendritic processes are responsible for the toxin directly entering the neuron. Using a 200 μl osmotic minipump, we administered 4 mg of MPTP HCl directly into the unilateral caudate nucleus, i.e., the dopamine nerve terminal area, of monkeys for 14 days. Persistent hemiparkinsonism began to appear in a week. Each monkey exhibited a flexed posture and hypokinesia of the contralateral limbs and circling toward the MPTP-treated side. These disturbances developed within 3 months and maintained a plateau for 3 months until the day of sacrifice. After treatment with apomorphine, there appeared a striking circling away from the MPTP-treated side. Selective cell loss in the MPTP-treated side of the substantia nigra pars compacta was found along the entire rostrocaudal extent relative to the untreated side. In conclusion, MPP + uptake only at the dopamine nerve terminals and retrograde axonal transport to the cell body seemed suffcient to destroy nigral dopamine cells in the monkey.