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A 69-year-old male (N.A.) with Creutzfeldt-Jakob disease showed pure autotopagnosia. We administered tests evaluating his ability to name his own body parts, to point to body parts (his own and examiner's), and to recognize positional relationships between his body parts by verbal questions and responses. We found impaired localization of the patient's own body parts by pointing and impaired recognition of positional relationships between his body parts. However, there was no impairment in naming his own body parts or in localizing the examiner's body parts. The results suggest a pure autotopagnosia in N.A. leading to an impairment of recognition of the spatial position of his body parts in a three-dimensional body representation within the egocentric reference frame. We were able to rule out the possibility that his pattern of performance could have been due to a disability in programming reaching movements of the arm.

ObjectiveTo evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).Methods373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset).ResultsNo significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months’ duration) showed longer time intervals to the primary event (pConclusionAlthough ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.Trial registration numberNCT00444613.

The aim of this study was to investigate the effects of tandospirone on ataxia in various types of spinocerebellar degeneration (SCD). Fifteen milligram per day of tandospirone was administered to 39 patients with SCD (spinocerebellar atrophy (SCA) 1, five patients; SCA2, six patients; Machado-Joseph disease (MJD), 14 patient; SCA6, five patients; multiple system atrophy-cerebellar type (MSA-C), seven patients; and multiple system atrophy-Parkinson type (MSA-P), two patients). All patients were assessed before and 4 weeks after administration of the drug using the international cooperative ataxia rating scale total score (ARS), total length traveled (TLT) of body stabilometry, and a self-rating depression scale. Statistically, ARS showed a significant difference in MJD (p = 0.005) and SCA6 (p = 0.043). TLT also showed a significant difference in MJD (p = 0.002) and SCA6 (p = 0.043). Eight of 39 patients (SCA1, 1/5; SCA2, 0/6; MJD, 4/14; SCA6, 3/5; MSA-C, 0/7; and MSA-P, 0/2) showed more than a five point reduction in ARS, and 13 of 39 patients (SCA1, 0/5; SCA2, 1/6; MJD, 8/14; SCA6, 4/5; MSA-C, 0/7; and MSA-P, 0/2) showed a reduction of TLT. Our data indicate that the effects of tandospirone on ataxia are different between types of SCD. Therefore, tandospirone is useful for cerebellar ataxia in patients with MJD and SCA6.

ピック病が疑われる病初期の語義失語症例におけるカテゴリー特異的意味障害について検討した。症例は 63 歳右利き女性，喚語困難で発症し，呼称および聴理解障害の進行を呈した。失語症語彙検査の意味カテゴリー別名詞検査を用いて検討し，聴理解では，初回はすべてのカテゴリーで差がなく障害は軽度であった。16 ヵ月後には，「身体部位」「色」「屋内部位」「建造物」は比較的良好であったが，「野菜・果物」「植物」「動物」「道具」「乗り物」「加工食品」に低下がみられた。生物カテゴリーでは，すべてのカテゴリーにおける障害がみられたが，非生物カテゴリーにおいては，カテゴリーによる乖離がみられた。本症例のカテゴリー特異的意味障害より，意味処理系は生物と非生物カテゴリーに二分されていない可能性，さらに各カテゴリーの意味処理機構と左側頭葉前部との関連性が示唆された。

SCA1 is a dominant spinocerebellar ataxia (SCA) and a multi-systemic syndrome caused by abnormal expansion of unstable CAG repeat in a novel gene located on chromosome 6p22-p23. We clinically studied 35 Japanese SCA1 patients who were assumed to have come from a common origin. The age at onset ranged from 15-63 years, and significantly correlated with CAG repeat units of mutant alleles. Ataxia was the initial symptom, and the majority of patients had a similar history of signs and symptoms. Nystagmus was at first minimal, later attenuated, and a slow saccade followed. Limb tendon reflexes were mostly hyperactive and depressed with the development of diffuse amyotrophy. The cardinal feature was ataxia-hyperreflexia-late slow saccade syndrome with terminal amyotrophy. Although the phenotype of SCA1 overlaps with those of other dominant SCAs, some facets of the neurological events differ from either SCA2 with ataxia-hyporeflexia-slow saccade syndrome, or early-onset Machado-Joseph disease with dystonia-bradykinesia-spasticity syndrome.

A 72-year-old man with pure topographical disorientation following a focal hemorrhage in the right forceps major of splenium was assessed at 2 weeks and 3 months after the onset. Initially, he could identify familiar buildings and landmarks, but noted topographical disorientation, dysfunction in sense of quarters, and in visuo-spatial function. The improvement of topographical disorientation was attained in 3 months, while the inability of the sense of quarters and manipulating visuo-spatial information remained unchanged. These results suggested the heading disorientation was accompanied with impaired sense of quarters, although disabled sense of quarters continued beyond the recovery of heading disorientation.

A 67-year old right-handed man with isolated left thumb paralysis was evaluated by transcranial magnetic stimulation and functional MRI. Recovery was observed in each neurophysiological examination, corresponding to neurological recovery of his thumb function.

Objective: To assess the efficacy of interferon beta-1b (IFNB-1b) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS). Background: The effects of IFNB in RRMS have been assessed in study populations comprised predominantly of white patients. MS in Japanese patients is different from that in white patients in that there are two different presentations—classic MS (C-MS) and optic-spinal MS (OS-MS)—and chronic progressive forms are infrequent. Methods: A total of 205 Japanese patients with RRMS were randomized to receive 50 μg or 250 μg (1.6 or 8.0 MIU) IFNB-1b administered SC every other day for up to 2 years. The primary endpoint was annual relapse rate. Secondary endpoints included further relapse-related and MRI outcome measures, as well as changes in Expanded Disability Status Scale and Neurologic Rating Scale. Efficacy was assessed in 188 patients, and safety was assessed in 192 patients. Supplemental ad hoc subgroup analyses were also performed for patients with OS-MS and those with C-MS. Results: Annual relapse rates were 0.763 in the 250 μg group and 1.069 in the 50 μg group, a relative reduction of 28.6% ( p = 0.047). Results for all secondary endpoints favored 250 μg IFNB-1b. Subgroup analyses suggested that the magnitude and direction of treatment effect in patients with OS-MS and C-MS was similar, albeit not significant due to small sample size. Conclusions: Interferon beta-1b (IFNB-1b) 250 μg significantly reduced relapse rates and change in MRI lesion area in Japanese patients with relapsing-remitting multiple sclerosis, and seemed to be comparably effective in optic-spinal multiple sclerosis (MS) and classic MS. The response to treatment with IFNB-1b in Japanese patients with MS suggests that a common pathogenesis and underlying genetic characteristics are shared with white patients.

Objective To determine the efficacy and safety of unilateral deep brain stimulation on the posterior subthalamic white matter, including the zona incerta (ZI) and the prelemniscal radiation (PRL), for tremor-dominant parkinsonian patients and to determine the exact location of electrodes that were most effective. Methods Eight parkinsonian patients with severe resting tremor underwent unilateral stimulation of the ZI/PRL by use of stereotactic guidance. Electrophysiological targeting was obtained by macrostimulation and by somatosensory evoked potentials recorded directly through a quadripolar deep brain stimulation lead. Postoperative computed tomographic scans and magnetic resonance images were performed to confirm anatomic location of the electrode. Parkinsonian motor disabilities were evaluated by use of the Unified Parkinson's Disease Rating Scale in the medication-off state before surgery and every 6 months after electrode implantations. Results The mean location of the clinically effective contacts was in the posterior subthalamic white matter, including the ZI and the PRL (mean, 5.6 +/- 1.2 mm posterior to the midcommissural point, 3.2 +/- 1.1 mm inferior to the anterior commissure-posterior commissure line, and 10.5 +/- 1.2 mm lateral to the midline). At 24 months after operation, ZI/PRL stimulation resulted in significant improvement in mean Unified Parkinson's Disease Rating Scale motor score by 44.3%, contralateral tremor by 78.3%, contralateral rigidity by 92.7%, and contralateral akinesia by 65.7% above the "off-stimulation" scores. Handwriting, posture, and gait were also improved. There were no or only mild adverse events. Conclusion Unilateral ZI/PRL stimulation is a reliable and long-term therapeutic modality and can be considered another surgical target for the treatment of tremor-dominant Parkinson's disease.

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.

Post-encephalitic parkinsonism has been well documented by now. Recently, an Indian group reported some post-encephalitic parkinsonism patients that resembled Japanese encephalitis cases with bilateral substantia nigra lesions that were detected by MRI. Post-encephalitis parkinsonism has been described following Coxsackie B virus, influenza A, poliovirus and measles virus infections. The possible involvement of virus infection has also been supported by experimental animal models. We have demonstrated pathological and to a certain extent clinical features consistent with Parkinson's disease following infection of rats with Japanese encephalitis virus (JEV). We evaluated new treatments with Parkinson's disease using this model. It was reported that tremor primarily involving the fingers, tongue and eyelids, muscle rigidity and masked face as the clinical features by JEV. Recently brainstem lesions produced by West Nile virus, which is a flavivirus like JEV, were documented by MRI. In the future, post-encephalitic parkinsonism may be found elsewhere in the world. In adult Fischer rats sacrificed 12 weeks after infection with JEV at the age of 13 days, neuronal loss with gliosis was confined mainly to the zona compacta of the bilateral substantia nigra, without lesions in the cerebral cortex and cerebellum. Furthermore, the most severe lesions were in the central part of zona compacta; the lateral cell groups were less affected. Thus, the distribution of the pathologic lesions in infected rats resembled those found in Parkinson's disease. JEV-infected rats showed marked bradykinesia. Significant behavioral improvement was observed upon administration of L-DOPA and monoamine oxidase (MAO) inhibitor. The findings suggest that JEV infection of rats under the conditions described may serve as a model of virus induced Parkinson's disease.

We evaluated the association of the plasma platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphism (G994→T) and PAF-AH activity with susceptibility and severity of multiple sclerosis (MS) in Japanese. DNA was collected from 216 patients with clinically definite MS (65 opticospinal MS (OS-MS) and 151 conventional MS (C-MS)) and from 213 healthy controls. The missense mutation G994→T that disrupts the PAF-AH activity was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No statistically significant difference in the frequency of genotypes and alleles of the plasma PAF-AH polymorphism was observed among OS-MS patients, C-MS patients and healthy controls. However, the missense mutation tended to be associated with the severity of OS-MS, especially in females (GT/TT genotypes; 51.7% in female rapidly progressive OS-MS vs. 26.6% in female controls, p=0.0870). Moreover, PAF-AH activities were significantly lower in MS than in controls, irrespective of clinical subtypes, among those carrying the identical polymorphism in terms of nucleotide position 994 of the PAF-AH gene. These findings suggest that the PAF-AH gene missense mutation has no relation to either susceptibility or severity of C-MS, yet its activity is down-regulated, and that the mutation has no relation with susceptibility of OS-MS, yet it may confer the severity of female OS-MS.

We previously reported that exogenously administered isatin, an endogenous monoamine oxidase (MAO) inhibitor, significantly increased acetylcholine (ACh) and dopamine (DA) levels in the rat striatum. Selegiline [(-)-deprenil] was developed as a MAO-B inhibitor more than 30 years ago and widely used in the treatment of Parkinson's disease. Effects of isatin or selegiline were investigated in Japanese encephalitis virus (JEV)-induced post-encephalitic parkinsonism rats by a pole test for detecting motor activity and by the determination of biogenic amine levels. Motor activity of JEV-induced rats receiving isatin (100 mg/kg per day for 1 week, i.p.) or selegiline (0.2 mg/kg per day for 1 week, i.p.) was significantly improved compared with that of untreated JEV-infected rats. Both isatin and selegiline prevented the decrease in striatal DA levels in JEV-rats. The increased turnover of DA (DOPAC/DA) induced by JEV was significantly inhibited by isatin, but not by selegiline. These results suggested that exogenously administered isatin and selegiline can improve JEV-induced parkinsonism by increasing DA concentrations in the striatum.

Background We investigated the frequencies of the symptoms such as "ataxia, depression, insomnia, anorexia, and pain," that have been reported to be associated with 5-HT1A receptor, and the effect of tandospirone citrate (tandospirone: 5-HT1A agonist) in patients with Machado-Joseph disease (MJD). Methods Ten MJD patients received tandospirone (15-30 mg/d) for seven weeks. During that time, they were evaluated weekly using the Ataxia Rating Scale (ARS) and Total Length Traveled (TLT) by Stabilimetry tests, the Self-rating Depression Scale (SDS), which in addition to evaluating their level of depression, also evaluated their degree of insomnia and anorexia, and a pain questionnaire. Results Before tandospirone therapy, all patients displayed cerebellar ataxia, while insomnia, and leg pain was observed in 7 patients, depression in 6 patients, and anorexia was observed in 2 patients. In response to treatment, 7 of the 10 patients who were ataxic showed a reduction in their ARS, while 3 of 6 patients showed a reduction in their SDS, and 5 of 7 patients showed an alleviation of their insomnia and leg pain. Both of the affected patients showed a marked improvement in their anorexia. A stabilimetry test could be performed in 7 patients, 5 of whom showed a reduction in TLT. Conclusions Our data indicate that the patients with MJD are prone to manifest 5-HT1A receptor-associated symptoms, and tandospirone is a useful drug for these symptoms in patients with MJD, though a double-blind study is needed.

Using the dual task paradigm, previous studies have suggested that working memory (WM) deficit is due to depleted attention resources in patients with Parkinson's disease (PD). The aim of this study is to establish whether the WM problems in PD are due to reduced attentional set-shifting resources rather than depletion of attention resources. The task design attempts to eliminate confounding of the deficits in dealing with novel material, a problem documented in PD, by concentrating on WM tasks of mental calculation that are familiar to subjects in daily living. We also administered attention tasks, the Trail Making Test (TMT) that relies primarily on attentional set-shifting and the Kana (Japanese syllabogram) Pick-out Test instead primarily depending on depleted attention resources for allocation. A total of 24 patients with PD and 24 normal controls participated in this study. The PD group showed deficits in mental calculation span and in attentional set-shifting in the TMT-b.Considering the common deficits in alternating processing of mental calculation and TMT-b in PD, the results suggested that the central executive dysfunction in PD during mental calculations was due to reduced attentional set-shifting resources for rapidly alternating operations, rather than the depletion of attentional resources.

This study investigated the neural mechanisms involved in the writing of Arabic numerals, kanji, and kana. Tasks involving writing numerals in Arabic, kanji, and, kana were administered to four patients with Gerstmann's syndrome and to five Wernicke aphasics. The results indicated that the ability to write Arabic numerals was well preserved in the Wernicke aphasics despite their serious phonological disturbances. The patients with Gerstmann's syndrome, who have a deficit with the concept of number, could write kanji numerals better than Arabic and kana numerals. Unlike Arabic numerals (ideogram) and kana (syllabogram), kanji (morphogram) have both semantic and phonetic values. The results suggested that Arabic numerals may be somesthetic and linked directly to the concept of number bypassing phonological analysis.

To investigate the frequency of positioning nystagmus in degenerative ataxic disorders, we examined downbeat positioning nystagmus (DPN) in 25 patients with spinocerebellar ataxia type 6 (SCA6) and 58 patients with other types of degenerative ataxia. DPN was observed in 21 of the 25 patients with SCA6 (84 %) versus only 3 of the 58 patients (5.2 %) with other types of degenerative ataxia, including multiple system atrophy, SCA1, SCA2, SCA3/Machado-Joseph disease, and non-SCA6 late-onset pure cerebellar ataxia. Our findings indicated that DPN is a distinct part of the clinical presentation of SCA6, showing that vestibular cerebellum is more affected in SCA6 than other types of degenerative ataxia.

Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p0.0001), and C allele was more prevalent in MS than in control (p0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/-8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.

Background: Oligoclonal IgG bands (OCB) are present in most patients with MS in Western countries; however, in Japanese MS patients, the OCB-positive rate is not as high. A relationship between immunogenetic backgrounds, namely, human leukocyte antigen (HLA) DR2 and DR4 positivity, and OCB production in MS patients from Hokkaido, the northernmost island of Japan, has been previously suggested by the authors.Objectives: To investigate the role of OCB in Japanese MS and to verify the interaction between immunogenetic backgrounds and OCB positivity.Methods: OCB, DR2(15), and DR4 positivity were studied in 45 patients with newly diagnosed MS. In addition to confirming the authors’ previous findings, the clinical and demographic features, MRI findings, OCB positivity, and DRB1*15 and DRB1*04 polymorphisms of an expanded data set of 99 MS patients were investigated by using multivariate analysis. Patients with opticospinal MS (OS-MS) were excluded from this study.Results: A relatively low OCB-positive rate (53.3%), HLA-DR15 association with OCB-positive MS (p = 0.0044), and DR4 association with OCB-negative MS (p = 0.0410) were confirmed. DR15 was not associated with OCB-negative MS. Demographic features, disease course, and disability were similar in the OCB-negative and OCB-positive group, whereas there was a preponderance of women in the OCB-positive group. An independent negative association of DRB1*0405 (p = 0.0021, adjusted odds ratio = 0.21) with OCB positivity was found.Conclusions: MS is heterogeneous in its association with HLA alleles, and based on the immunogenetic differences, the MS patients in this population include at least two HLA-related subpopulations with and without OCB.

Proteasomal dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). We examined the effect of a selective proteasomal inhibitor, epoxomicin, on primary cultured mesencephalic neurons. Exposing rat cultured mesencephalic neurons to epoxomicin for 24 h resulted in neurotoxicity in a dose-dependent manner. Epoxomicin caused mitochondrial dysfunction, reduction in reduced glutathione (GSH), and increased generation of free radicals. Neuronal damage was significantly blocked by antioxidative/GSH-augmenting agents. Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals. Dopaminergic neurons were preferentially resistant to the toxicity of epoxomicin. Inhibiting the synthesis of tetrahydrobiopterin (BH(4)), which has been reported to have antioxidative function, increased the susceptibility of dopaminergic neurons, whereas increasing BH(4) levels protected non-dopaminergic neurons. These findings suggest that BH(4) is at least in part a contributing factor to grand the resistance to dopaminergic neurons against epoxomicin neurotoxicity. Our results suggest that proteasome inhibition causes the neurotoxicity in mesencephalic neurons, but that is not sufficient to reproduce the selective damage to dopaminergic neurons, such as that seen in PD.

Brefeldin A (BFA) is a fungus metabolite that is known to cause the disassembly of the Golgi complex and apoptosis in exposed cells, both of which have been suggested as playing roles in the pathogenesis of neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS). This study showed that BFA caused neurotoxicity and apoptotic nuclear changes in cultured spinal neurons of rat spinal cord in a dose- and time-dependent manner. The spinal motor neurons were more vulnerable to this neurotoxicity. The cultured spinal neurons showed irreversible disassembly of the Golgi apparatus as early as 1 hr after exposure to BFA. BFA induced the expression and activation of caspase-12 beginning 8 hr after exposure. The level of the cleaved form of caspase-3 had increased 12 hr after the addition of BFA. Free radical generation and loss of mitochondrial membrane potential were observed in the later stages of neurotoxicity caused by BFA. Collectively, our data suggests that BFA is an excellent agent for reproducing the pathophysiological features of ALS. This in vitro model may be useful in attempts to study the mechanisms of this neurodegenerative disease and to examine therapeutic potentials.

Isatin, an endogenous monoamine oxidase (MAO) inhibitor, has an important role in the control of neurotransmitter concentration. We previously reported that exogenously administered isatin significantly increased acetylcholine (ACh) and dopamine (DA) levels in the rat striatum. In order to test the possibility of treating Parkinson's disease by isatin, we evaluated DA levels in the striatum and bradykinesia using a rat model of Parkinson's disease induced by the Japanese encephalitis virus (JEV). We have already reported that in adult Fischer rats infected with JEV at day 13, there was a marked decrease of tyrosine hydroxylase-positive neurons in the bilateral substantia nigra after 12 weeks. Effects of isatin were investigated in JEV-induced post-encephalitic parkinsonism rats by a pole test and high performance liquid chromatograph (HPLC) with an electrochemical detector (ECD). Isatin (100 mg/kg per day for 1 week, intraperitoneal injection) improved the bradykinesia observed in the JEV-induced parkinsonism rats. Dopamine (DA) concentrations in the JEV-infected rats were profoundly reduced in the striatum as compared with controls. Isatin also increased DA in the striatum of parkinsonism rats. These results suggest that isatin could be a possible treatment for Parkinson's disease as well as for post-encephalitic parkinsonism.

In Japan, multiple system atrophy (MSA) accounts for 40% of all spinocerebellar ataxias (SCAs) and hereditary disorders account for 30%. Among the latter, autosomal dominant disorders are common and recessive ataxias are rare. Although the frequency of SCA genotypes differs between geographic regions throughout Japan, SCA6, SCA3/MJD, and DRPLA are the three major disorders, while SCA7, SCA8, SCA10, SCA12, and SCA17 are infrequent or almost undetected. SCA1 predominantly occurs in the northern part of Japan. Overall, 20–40% of dominant SCAs are due to unknown mutations. From this cluster, pure cerebellar ataxias linked with the SCA4, SCA14, and SCA16 locus have been isolated. Among the recessive SCAs, patients with AVED and EAOH have been detected. However, FRDA associated with GAA repeat expansion in the frataxin gene has not been reported so far.

Interleukin-2 (IL-2) is a cytokine intimately involved with both the function and regulation of the immune system. Genetic analysis of experimental autoimmune encephalomyelitis (EAE) provides strong evidence supporting the candidacy of IL-2 as a susceptibility gene. We investigated the association of two single nucleotide polymorphisms (SNPs) at position -384 in the promoter region and +114 in the first exon of the IL-2 gene through a case-control study involving 113 Japanese patients with multiple sclerosis (MS) and 118 healthy controls. Our results showed no significant differences in the distribution of the two polymorphisms between MS patients and controls. Furthermore, no association was observed between IL-2 gene polymorphisms and clinical characteristics, such as clinical course and age at disease onset. Together, our findings suggest that IL-2 gene polymorphisms do not influence the susceptibility to MS or the clinical characteristics of MS in Japanese patients.

In adult Fischer rats sacrificed 12 weeks after infection with Japanese encephalitis virus (JEV) at the age of 13 days, neuronal loss with gliosis was confined mainly to the zona compacta of the bilateral substantia nigra, without lesions in the cerebral cortex and cerebellum. Furthermore, the most severe lesions were in the central part of zona compacta; the lateral cell groups were less affected. In addition, immunohistochemical study with anti-tyrosine hydroxylase (TH) showed that the number of TH-positive neurons was decreased significantly in the substantia nigra compared with that in controls, while comparable TH-positive neurons were found in the basal ganglia in the JEV-treated rats and age-matched controls. Thus, the distribution of the pathologic lesions in infected rats resembled those found in Parkinson's disease. The immunohistochemical studies failed to detect JEV antigens in any region of the rat brain and the JEV genome was undetectable in the substantia nigra and the cerebral cortex by reverse transcription-polymerase chain reaction. JEV-infected rats showed marked bradykinesia. Significant behavioral improvement was observed upon administration of L-DOPA. The findings suggest that JEV infection of rats under the conditions described may serve as a model of virus induced Parkinson's disease. We could evaluate the possibilities of some new drugs using this rat model.

We investigated PvuII and XbaI polymorphism in the estrogen receptor gene (ERG) and HLA-DRB1*1501 positivity in 116 conventional multiple sclerosis (MS) patients and 101 healthy controls in a Japanese population. Logistic analysis revealed independent associations of [P] allele in the profiles for PvuII (p=0.0005, adjusted odds ratio (aOR)=3.17) and DRB1*1501 (p=0.0089, aOR=2.61) with conventional MS. Synergistic elevated risk of MS due to interaction between the [P] allele and HLA-DRB1*1501 allele was found among female patients (odds ratio=16.0; 95% CI=3.99-63.8, p

INTRODUCTION The involvement of glycation in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) was recently indicated. We previously reported the existence of an Amadori product, 1-hexitol-lysine (1-HL), which is formed in the early glycation reaction, in axonal spheroids of the anterior horn of the ALS spinal cord. OBJECTIVE The purpose of the present study was to confirm the occurrence of the later-stage glycation reaction that follows the early glycation reaction and leads to the formation of advanced glycation end products (AGEs). METHOD We examined whether N(epsilon)-(carboxymethyl)lysine (CML) and non-CML AGE are present in ALS spinal cords. RESULTS Immunohistochemical staining with anti-CML antibody revealed intense positivity in the cell bodies of the remaining atrophic motor neurons and in microglia. Microglia were also positive on staining with anti-non-CML antibody. Axonal spheroids were also positive on anti-non-CML-antibody staining. Vascular endothelial cells were slightly stained by both antibodies. CONCLUSIONS The presence of non-CML AGE in the anterior horn of the ALS spinal cord indicates that the later stage of the glycation reaction is involved in the pathology of ALS. The presence of CML in the anterior horn was also confirmed, and this may reflect augmented oxidative stress.

In daily clinical practice we noticed that patients with intellectual impairment spontaneously flex the elbow within a few seconds of the forearm being manipulated during routine examination of spasticity of the muscles in the upper extremities. We termed this phenomenon elbow flexion response (EFR), and prospectively studied it in 229 patients who underwent in-hospital rehabilitation following brain damage. Evaluation of each patient included EFR, patient profile, ability to communicate, scores on three parameters from various intelligence tests, scores on seven parameters testing primitive reflexes, and scores on three parameters describing personality. We investigated for relationships among these parameters. Consequently, although EFR rarely have a statistical association with the varied profiles of patients, patients with bilateral lesion or bilateral paresis demonstrated significantly more marked EFR than those with unilateral lesion or unilateral paresis. Patients with involvement of the frontal lobe showed significantly more marked EFR than those without damage in this area. Elbow flexion responses occurred significantly more frequently in relation with lower scores on intelligence and occurred with significantly higher frequency in conjunction with the more marked appearance of conventional primitive reflexes. Therefore, we conclude that EFR have a strong association with intelligence and with the existence of frontal lobe lesion, and their mode of clinical presentation parallels that of primitive reflexes particularly that of the grasp reflex. We propose that EFR could be referred as a variation of the grasp reflex occurring in the more proximal or axial part of the body.

Tandospirone citrate (tandospirone) is an anti-anxiety drug that acts by combining with serotonin receptor (5-hydroxytryptamine-1 A [5-HT1A]). Recently, there have been a few reports of its potential role in the treatment of cerebellar ataxia. We report the first case of a patient with Machado-Joseph disease in which we successfully treated cerebellar ataxia. In addition, his leg pain, insomnia, anorexia, and depression, which are thought to be related to 5-HT1A receptors, were also remarkably alleviated by treatment with tandospirone.

As there is a risk of MTCT of HTLV-1, the HSGP HTLV-1 MTCT was organized in 2011. To determine how many pregnant women are infected with HTLV-1 in Hokkaido, which is the northernmost and the second largest island in Japan with a population of 5,467,000 and 39,392 newborns in 2011, the HSGP HTLV-1 MTCT asked all facilities that may care for pregnant women in Hokkaido in July 2013 to provide information on the number of pregnant women who underwent screening for anti-HTLV-1 antibody using particle agglutination or chemiluminescent enzyme immunoassay, and the numbers of those with positive, equivocal, and negative test results in the screening and confirmation tests using western blotting or PCR methods in 2012, respectively. A total of 111 facilities participated in this study and provided information on 33,617 pregnant women who underwent screening in 2012, corresponding to approximately 85% of all pregnant women who gave birth in Hokkaido in 2012. Of 81 candidates for a confirmation test because of positive (n = 77) or equivocal (n = 4) results on screening, 63 (78%) underwent the confirmation test and, finally, 34 (0.1%) and 33,563 (99.8%) women were judged to be HTLV-1 carriers and non-carriers, respectively. It was concluded that the prevalence rate of HTLV-1 carriers was low, one per 1000 pregnant women in Hokkaido. Approximately 40 infants are born yearly to mothers infected with HTLV-1 in Hokkaido.

In the present study, we have investigated the association of specific polymorphisms of the interleukin (IL)-1beta and IL-1 receptor antagonist (ra) gene with both the susceptibility to and the clinical characteristics of multiple sclerosis (MS) in Japanese patients. We collected and analyzed DNA from 98 MS patients and 104 healthy controls for distribution of IL-1beta or IL-1ra polymorphisms. Our results show no significant differences in the distribution of the polymorphisms between MS patients and controls. Furthermore, no association was observed between IL-1beta or IL-1ra polymorphisms and clinical characteristics, such as age at disease onset, clinical course and severity. Together, our findings suggest that IL-1beta or IL-1ra gene polymorphisms may not be relevant in the susceptibility to MS or the clinical characteristics of Japanese patients with MS.

Despite the strength of the association of multiple sclerosis (MS) and human leukocyte antigen (HLA)-DR2, other genetic elements could have a role in the pathophysiology of MS. We investigated possible associations with polymorphic susceptibility genes located within the HLA complex, i.e., heat-shock protein (HSP)70-1, HSP70-2, and HSP70-hom in Japanese patients with MS. Furthermore, we analyzed the influence of HSP70 gene polymorphisms on the severity of the disease, clinical course, magnetic resonance imaging findings, and oligoclonal bands in the cerebrospinal fluid, and HLA in MS patients. The results of the present study indicated that there were no significant differences in the distribution of all HSP70 genotypes and allele frequencies between Japanese MS patients and controls. In MS patients, there were no associations between HSP70 gene polymorphisms and the clinical data. Moreover, there were no significant differences in HSP70 genotype or allele frequencies between MS patients positive for HLA-DRB1*1501 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms are not relevant in the susceptibility to or the severity of Japanese MS patients.

Objective To investigate the effect of acetazolamide on spinocerebellar ataxia type 6 (SCA6). Methods Acetazolamide (250-500 mg/day) was administered orally for 88 weeks to 6 patients with SCA6, and its effect was quantitatively monitored using the Ataxia Rating Scale (ARS) and body sway analysis by stabilometry. Results During administration of acetazolamide, the ARS score and the amplitude of body sway were significantly reduced compared with before administration. However, the response became weaker after 1 year of treatment. Conclusion Although this was an open trial, the results suggested that acetazolamide can temporarily reduce the severity of symptoms during the progression of SCA6.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, plays a critical role in adipocyte differentiation and glucose homeostasis. It has been implicated that PPAR-gamma functions as a regulator of cellular proliferation and inflammatory responses. In the present study, we examined whether troglitazone, a selective PPAR-gamma agonists, ameliorated experimental autoimmune encephalomyelitis (EAE) induced by administration of myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 in C57BL/6 mice. We found that troglitazone attenuated the inflammation and decreased the clinical symptoms. It was suggested that the amelioration was attributed to the attenuation of pro-inflammatory cytokine gene expressions.

Macrophage migration inhibitory factor (MIF) is becoming increasingly recognized as an important regulator of immune and inflammatory responses. It is released by activated T lymphocytes and macrophages and up-regulates the proinflammatory activity of these cells. MIF is required for antigen- and mitogen-driven T cell activation, and stimulates macrophages to release cytokines and nitric oxide. On the basis of the recent suggestion that pharmacological modulation of MIF production and neutralization of its activity may have important implications for treatment of a variety of autoimmune or inflammatory conditions, we determined the level of MIF in the cerebrospinal fluid (CSF) of patients with conventional-form multiple sclerosis (C-MS) and optic-spinal form multiple sclerosis (OpS-MS), and neuro-Behcet's disease (NBD). As control, the CSF of patients with non-inflammatory neurological diseases (NIND) was used. The concentration of MIF in CSF samples was significantly elevated in relapsed cases of C-MS (4.13+/-1.07 ng/ml) (mean+/-S.D.) compared with control samples (2.38+/-0.60 ng/ml) (P

Dominantly inherited, late-onset pure cerebellar ataxia is a group of genetically heterogeneous neurodegenerative disorders. Approximately half of these disorders in the Japanese population are caused by moderate expansion of a CAG repeat in the coding region of the CACNA1A gene on chromosome 19p13 (SCA6). However, neither the loci nor the specific mutations for the remaining disorders have been determined. We performed systematic linkage analysis in a three-generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. The family members with a late onset (≥39 years old) exhibited pure cerebellar ataxia, whereas those with an early onset (≤27 years old) first showed intermittent axial myoclonus followed by ataxia. Other neurological signs were sparse, and neuroimaging studies revealed that atrophy was confined to the cerebellum. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter (Zmax = 4.08, corrected for age-dependent penetrance). Ann Neurol 2000;48:156–163

We investigated a consanguineous Japanese family with a complicated form of familial spastic paraplegia (FSP). Three siblings were affected, probably by autosomal recessive inheritance. All showed ataxia, subnormal mentality, congenital cataracts, and slight cerebellar atrophy on CT scans. Spastic paraplegia was predominant in 2 siblings, while ataxia was more marked in the other. Slight but definite atrophy of the corpus callosum and axonal neuropathy were demonstrated in 1 sibling who underwent detailed investigation. Review of similar cases reported in the literature indicates that this recessively inherited disorder probably represents a homogeneous group within the heterogeneous cluster of complicated FSP.

Approximately 44% of cases of spinocerebellar ataxia (SCA) in Hokkaido, the northernmost island of Japan, were estimated to be inherited. To determine the prevalence of triplet repeat expansion in hereditary SCA patients, we genotyped seven genetically defined dominant SCAs in 349 patients, including 266 patients from 77 families, 78 probands from unrelated families with hereditary late-onset SCA, and five patients in whom a family history of SCA was not demonstrated. The frequency of each disorder in a total of 155 unrelated families was 23.9% for Machado–Joseph disease (MJD), 29.0% for SCA6, 9.7% for SCA1, 7.7% for SCA2, and 2.6% for dentatorubral–pallidoluysian atrophy. Abnormal expansion of triplet repeats for SCA7 and SCA8 was not detected. A total of 27.1% of the patients had still unknown SCA mutations. In addition, the GAA repeat in the frataxin gene was not abnormally expanded in 13 early-onset SCA patients with clinical features similar to those of Friedreich ataxia. Comparison of our results with those from other centers handling SCA showed that MJD is prevalent throughout Japan, but the frequencies of other dominant SCAs differ considerably even within Japan.

The polymorphism of ¶the HLA class II genes was investigated in 97 patients with multiple sclerosis (MS) in Hokkaido, the northernmost main island of Japan. Of these, 80 patients were classified as having conventional MS and 17 ¶as having opticospinal MS (OS-MS). Our findings confirmed a previous report that the DPB1*0501 allele is positively associated with OS-MS ¶(P = 0.0043). The frequency of DPB1*0501 was also found to be higher in conventional MS patients than in controls (79% vs. 58%, ¶P = 0.0084), although the differences were not statistically significant. Our results indicate that OS-MS is a DPB1*0501-associated subgroup of MS, and that DPB1*0501 is also correlated with risk of conventional MS in Japanese.

The purpose of this study was to clarify the association of HLA-DRB1 and -DPB1 alleles with multiple sclerosis (MS) in Japanese, to determine whether optico-spinal MS (OS-MS) and conventional MS are immunogenetically distinct, and to verify the role of gender difference in HLA associations of MS. We studied HLA-DRB1 and -DPB1 polymorphisms in 166 Japanese patients with MS. Forty-seven patients were classified as having the optico-spinal MS (OS-MS) and 119 as having conventional MS. A lack of DPB1*0301 and a higher frequency of DPB1*0501 compared with controls (corrected P

Glycation is a series of non-enzymatic reactions initiated by addition of reducing sugars to epsilon-amino group of lysine residues and alpha-amino group of the N terminus of proteins, leading to the formation of advanced glycation end products (AGE). It is thought to be involved in aging and various neurodegenerative conditions. In the present study using anti-1-hexitol-lysine (1-HL) antibody, Amadori product, an early glycation product, was detected in axonal spheroids in the anterior horn of amyotrophic lateral sclerosis and in atrophic neurons of spinobulbar muscular atrophy (SBMA, Kennedy disease with abnormally expanded triplet repeats in androgen receptor gene) but not in other regions of the central nervous system. Furthermore, Amadori product was undetectable in the tissues from age-matched controls. Thus, 1-HL formation could not reflect physiological aging.

A decrease in intracellular glutathione content may be related to the primary event in Parkinson's disease, so increasing the glutathione level may have a therapeutic benefit. The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been recently reported to enhance the intracellular glutathione concentration in the central nervous system. Exposing rat cultured mesencephalic neurons for 24 hr to a mixture of L-buthionine sulfoximine (BSO) and 1-methyl-4-phenylpyridium ions (MPP+) resulted in a relatively selective damage to dopaminergic neurons. This damage has been accompanied by a reduction of intracellular glutathione levels. Low doses, i.e., 1–100 nM, of 1,25-(OH)2D3 protect cultured dopaminergic neurons against this toxicity, although higher concentrations of this active form of vitamin D have been found to enhance the toxic effect. Generation of reactive oxygen species (ROS) by this toxicity has been attenuated in cultures being pretreated with low concentrations of 1,25-(OH)2D3. Because the hormone increases the intracellular glutathione content in cultures, determining how this hormone suppresses ROS generation may involve the enhancement of the antioxidative system. These data suggest that low doses of 1,25-(OH)2D3 are able to protect mesencephalic dopaminergic neurons against BSO/MPP+-induced toxicity that causes a depletion in glutathione content. J. Neurosci. Res. 62:374–382, 2000. © 2000 Wiley-Liss, Inc.

The clinical features of MS in Japanese are said to be characterized by high incidence of optico-spinal MS (OS-MS), although the frequency of it has recently decreased. The term OS-MS is used to describe a subgroup of patients diagnosed with MS, in which the clinically determined lesions are confined to the optic nerves and the spinal cord. The OS-MS is characterized by a female preponderance, a later onset, a higher score of the expanded disability status scale of Kurtzke (EDSS), milder abnormalities on brain MRIs, higher sero-positive rates for some autoantibodies, and higher cell counts and protein levels in the cerebrospinal fluid, compared with conventional MS. The OS-MS is positively associated with HLA-DPB1*0501 allele, and the HLA prohile are different between OS-MS and conventional MS. Therefore, the OS-MS is immunogenetically as well as clinically a distinct subtype of MS.

アテト一ゼとは, 1871年にHammondが提唱した不随意運動で,その意味するところは「安定した姿位を保つことができない」ということで,舞踏運動とは異なる概念として今日に至るまで意義のあるものである.その責任病巣は大脳基底核,とくに線条体である.しかしアテトーゼ様の不随意運動,舞踏アテトーゼ,舞踏運動をはじめ,類似そして鑑別に苦慮する不随意運動はいくつもあり,これらの病態,鑑別,そして治療の試みも含め検討すべき問題は多数存在していると言える.