Efficacy of Repetitive Trans-spinal Magnetic Stimulation for Patients with Parkinson's Disease: a Randomised Controlled Trial.

We evaluated the effect of repetitive trans-spinal magnetic stimulation (rTSMS) in patients with Parkinson's disease (PD) in a randomised, single-blind study. Participants were hospitalised and administered a single trial of rTSMS or sham treatment 2 days a week for 4 weeks. In addition, all participants underwent rehabilitation 5 days a week for 4 weeks. The primary outcome was the difference between the two groups in the mean change from baseline to post-training in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS). Secondary endpoints included the differences between the two groups in the mean change on the UPDRS part III (motor) score and the Timed Up and Go (TUG) score. Eligible participants were randomly assigned to either the rTSMS group (n = 50) or sham group (n = 50). The between-group difference in mean change in the total UPDRS score was 10.28 (95% confidence interval (CI), 4.42 to 16.13; P = 0.014) immediately after intervention from baseline, 5.04 (95% CI, - 5.41 to 15.50; P = 0.024) 3 months after intervention from baseline and 2.38 (95% CI, 7.18 to 11.85; P = 0.045) 6 months after intervention from baseline. Significant differences between groups in UPDRS part III and TUG scores were maintained more strictly than those in the UPDRS total score. These results strongly indicate that rTSMS promotes the effect of rehabilitation on motor function in patients with PD.

Sociability-based fitness approach in Parkinson's disease: Comparison with conventional rehabilitation.

BACKGROUND AND PURPOSE: The effect of a sociability-based fitness approach on parkinsonian disability in patients with Parkinson's disease (PD) was assessed. METHODS: Eighty patients diagnosed with PD were randomly assigned to either the group-based rehabilitation (GBR) group (n = 40) or the individual-based rehabilitation (IBR) group (n = 40). The primary outcome was the difference between the two groups in the mean change from baseline to post-training in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS). The secondary outcomes included the change in mental status and the difference in the mean change from baseline to month 3 and month 6 in the total score on the UPDRS. RESULTS: The mean (±SD) UPDRS scores were 72.0 ± 21.0 in the GBR group and 72.1 ± 18.6 in the IBR group. The UPDRS scores from baseline to post-training were 22.8 ± 13.5 in the GBR group and 10.9 ± 8.8 in the IBR group (difference 11.8 points; 95% confidence interval [CI] 5.0-18.6; p = 0.001). The difference between the groups from baseline to month 3 (difference 10.06 points; 95% CI 3.3-16.8) and the difference between the groups from baseline to month 6 (difference 11.7 points; 95% CI 4.9-18.5) were also significant (p = 0.004 and p = 0.001, respectively). The scores of cognitive function and depression had not changed significantly. CONCLUSIONS: Patients receiving GBR demonstrated significant improvements in parkinsonian symptoms, suggesting that the sociability-based fitness can be applied to clinical treatment by sustaining the motivation in PD.

A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability.

BACKGROUND: Hereditary cerebellar ataxia constitutes a heterogeneous group of neurodegenerative disorders, occasionally accompanied by other neurological features. Genetic defects remain to be elucidated in approximately 40% of hereditary cerebellar ataxia cases in Japan. We attempted to identify the gene responsible for autosomal recessive cerebellar ataxia with intellectual disability. METHODS: The present study involved three patients in a consanguineous Japanese family. Neurological examination and gene analyses were performed in all family members. We performed genome-wide linkage analysis including single nucleotide polymorphism arrays, copy-number variation analysis and whole exome sequencing. To clarify the functional alteration resulting from the identified mutation, we performed cell viability assay of cultured cells expressing mutant protein. RESULTS: One homozygous region shared among the three patients on chromosomes 2p16.1-2q12.3 was identified. Using whole exome sequencing, six homozygous variants in genes in the region were detected. Only one variant, VWA3B c.A1865C, results in a change of a highly conserved amino acid (p.K622T) and was not present in control samples. VWA3B encodes a von Willebrand Factor A Domain-Containing Protein 3B with ubiquitous expression, including the cerebellum. The viability of cultured cells expressing the specific K622T mutation was proved to decrease through the activation of apoptotic pathway. CONCLUSIONS: Mutated VWA3B was found to be likely associated with cerebellar degeneration with intellectual disability. Although a rare cause of cerebellar degeneration, these findings indicate a critical role for VWA3B in the apoptosis pathway in neuronal tissues.

Late-onset myasthenia gravis is predisposed to become generalized in the elderly.

OBJECTIVE: The continuous increase in the number of patients presenting with late-onset myasthenia gravis (LOMG) underscores the need for a better understanding of the clinical course and the establishment of an optimal therapeutic strategy. We aimed to clarify factors associated with clinical outcomes in LOMG. METHODS: We retrospectively reviewed the clinical profiles of 40 patients with early-onset MG (EOMG) (onset age: 49 years or younger), 30 patients with non-elderly LOMG (onset age: 50-64 years), and 28 patients with elderly LOMG (onset age: 65 years or older) and compared the subgroups according to onset age and thymus status. The evaluated parameters were MGFA classification before treatment, MG-ADL score, complicating diseases, antibody titer, treatment, and MGFA post-intervention status. RESULTS: Elderly LOMG patients showed transition to generalized symptoms at a higher frequency and underwent thymectomy less frequently than EOMG and non-elderly LOMG patients (p < 0.001). The frequencies of crisis and plasmapheresis were significantly lower in thymectomized LOMG patients without thymoma than in thymectomized LOMG patients with thymoma or non-thymectomized LOMG patients (p < 0.01, P < 0.05, respectively). However, the outcome was not significantly different. All of the thymectomized LOMG patients without thymoma presenting with hyperplasia or thymic cyst had a favorable clinical course. CONCLUSIONS: Our study showed that elderly LOMG patients are more prone to severity, suggesting that they require aggressive immunomodulatory therapy.

Immediate effect of spinal magnetic stimulation on camptocormia in Parkinson's disease.

OBJECTIVES: Spinal cord stimulation is a potential therapeutic option for the treatment of Parkinson's disease (PD)-associated symptoms. Repetitive trans-spinal magnetic stimulation (rTSMS) is a non-invasive and safe alternative for stimulation of spinal pathways that has not been studied for therapeutic efficacy in PD. We assessed the benefits of rTSMS on camptocormia, an often treatment-resistant postural abnormality observed in PD patients. METHODS: We compared rTSMS to sham stimulation in PD patients with camptocormia in a single-centre, randomised, single-blind, crossover, placebo-controlled study. PD patients with camptocormia were administered a single trial of rTSMS (a train of 40 stimuli) or sham treatment followed 1 week later by the alternate treatment. Primary outcome measure was thoracolumbar spine flexion angle in the standing position immediately after the trial. RESULTS: Of 320 PD patients examined, 37 had concomitant camptocormia and were randomly assigned to either the rTSMS first group (n=19) or sham first group (n=18). Flexion angle in the standing position decreased by a mean of 10.9° (95% CI 8.1 to 13.65) after rTSMS but remained unchanged after sham stimulation (mean, -0.1°; 95% CI -0.95 to 0.71). The flexion angle while sitting (secondary outcome) decreased by 8.1° (95% CI 5.89 to 10.25) after rTSMS, whereas sham treatment had no significant effect (mean, -0.8°; 95% CI -1.62 to 0.05). CONCLUSIONS: We found an immediate beneficial effect of rTSMS on camptocormia in PD patients. Although the effect was transient, this successful trial justifies further studies to test if repeated rTSMS treatments can induce longer term improvements in camptocormia associated with PD. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000011495.

Superoxide dismutase as a target of clioquinol-induced neurotoxicity.

Subacute myelo-optico-neuropathy (SMON) is a progressive neurological disorder affecting the spinal cord, peripheral nerves and optic nerves. Although it has been assumed that SMON was caused by intoxication of clioquinol, the mechanism underlying clioquinol-induced neurotoxicity is not fully understood. This study aimed to clarify the relevance of oxidative stress to clioquinol-induced neurotoxicity and the cause of the enhanced oxidative stress. Clioquinol induced cell death in human-derived neuroblastoma cell line, SH-SY5Y, in a dose-dependent manner. This process was accompanied by activation of caspase-3 and enhanced production of reactive oxygen species (ROS). We examined whether clioquinol inhibited the activity of superoxide dismutase-1 (SOD1), based on its metal chelating properties. Clioquinol inhibited activities of purified SOD1 in a dose-dependent manner. Cytosolic SOD activities were also inhibited in SH-SY5Y cells treated with clioquinol. Finally, addition of exogenous SOD1 to the culture significantly reduced enhanced ROS production and cell death induced by clioquinol in SH-SY5Y cells. These findings suggested that enhanced oxidative stress caused by inhibition of SOD1 undelay clioquinol-induced neurotoxicity and was relevant to the pathogenesis of SMON.

A new CSF1R mutation presenting with an extensive white matter lesion mimicking primary progressive multiple sclerosis.

HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. Genetic defects in the colony-stimulating factor 1 receptor (CSF1R) gene have been reported in many HDLS cases. The present report describes a new missense mutation Arg777Gln involving exon 18 of the CSF1R gene in a sporadic patient presenting with tumor-like lesions mimicking primary progressive multiple sclerosis. The patient was initially diagnosed with a progressive variant of multiple sclerosis and received inadequate treatments. Although most HDLS cases have a positive family history, this disease should also be suspected in sporadic patients showing unusual white matter lesions at MRI.

Participant preferences for the provision of registration trials results.

BACKGROUND: Clinical trials leading to drug approval (registration trials) play a central role in the drug development process, and attention has recently been paid to providing trial results to participants. In the present study, we examined the preferences of participants of registration trials for the provision of trial-related information. METHODS: We used questionnaires to survey the preferences of registration trial participants at Tokushima University Hospital and Tokushima National Hospital. Of the 15 questions, 6 related to participant characteristics and the trials in which they participated, while 9 questions were concerned with preferences for the provision of information. A five-point scale (strongly agree, agree, neutral, disagree, and strongly disagree) was used, and positive answers (strongly agree and agree) were considered to indicate a positive preference. RESULTS: Of the 58 subjects, 1 declined, giving a response rate of 98%. More than 70% of participants preferred to obtain information, even if they had served as controls. More than 80% of participants agreed to obtain information relating to trial results, even if the results were negative, and more than 80% of participants agreed to obtain information on the labeling state of the agent, even if development had ceased. Although more than 60% of participants agreed for the provision of information on their allocation and around more than 70% agreed to the provision of information on registration trials status, significantly fewer participants with difficult-to-treat diseases (for example, neurological and malignant diseases) agreed to obtain information compared with participants with other types of diseases (for example, acute, chronic, and psychological diseases). More than 50% of participants desired information to be provided directly by the physician, while a considerable number of participants desired information by means of clinical research coordinators (CRCs) (24.4%) or by posted letter (33.3%). CONCLUSION: The present results suggest the preferences for the provision of individual and overall information concerning research results. However, further study is warranted to determine participant preferences more precisely and the effect of the CRC-initiated infrastructure for providing information on patient satisfaction and for promoting registration trials.

[A case of neuromyelitis optica spectrum disorder developing a fulminant course with multiple white-matter lesions following fingolimod treatment].

A 49-year-old female neuromyelitis optica spectrum disorder (NMOSD) patient with positive anti-aquaporin 4 (AQP4) antibody was treated with fingolimod (FTY720). Ten days later, she developed acute disturbance of consciousness, aphasia, right hemi-spatial neglect, and right hemiparesis. Brain MRI showed multiple white-matter lesions with slight Gadolinium enhancement. She was diagnosed of acute exacerbation of NMOSD. Thus, fingolimod may be associated with the development of a fulminant course in NMOSD patients with positive anti-AQP4 antibody.

FK506 attenuates thymic output in patients with myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4(+) T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG. MATERIAL AND METHODS: We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants. RESULTS: T-cell receptor excision circle was not significantly different from those in age-matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4(-)CD8(+) cells (p < 0.05), but total cell counts were not significantly changed. CONCLUSIONS: These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also naïve T-cells.

Parkin interacts with Klokin1 for mitochondrial import and maintenance of membrane potential.

Parkin is a multifunctional protein, including maintaining mitochondrial homeostasis. Recent evidence suggests that Parkin is recruited from the cytoplasm to damaged mitochondria with low membrane potential. We found that intracellular localization of Parkin changed with cellular growth phase. Parkin was preferentially localized in the mitochondria of cultured cells. The mitochondria with large amounts of Parkin showed preserved membrane potentials even during treatment with carbonyl cyanide m-chlorophenylhydrazone. Here we report a novel protein named Klokin 1 that transports Parkin to the mitochondria. Klokin 1 was localized to the mitochondria and enhanced mitochondrial expression of Parkin. Klokin 1 enhanced cell viability in Parkin-silenced cells. Klokin 1 expression was enhanced in the brains of Parkin-deficient mice but not in an autopsied PARK2 brain. Our findings indicate that mitochondrial Parkin prevents mitochondrial depolarization and that Klokin 1 may compensate for Parkin deficiency.

The effects of FK506 on refractory inflammatory myopathies.

We performed an observational clinical study, the effects of tacrolimus (FK506) on the thymic output in patients with refractory inflammatory myopathies. Sixteen patients with polymyositis (PM) and 15 with dermatomyositis (DM) were treated orally with tacrolimus. Serum CK levels significantly decreased 2 to 4 months after tacrolimus therapy (p < 0.01), and MRC (Medical Research Council) scores were significantly improved 2 months after tacrolimus therapy (p < 0.01). T-cell receptor excision circle (TREC) content, a proxy for thymic export was not significantly different from that in age-matched controls, except for an increase in the TREC content within CD8+ single positive cells in patients with DM. TREC contents within double-positive cells and CD4+ single-positive cells were significantly decreased 4 M after tacrolimus therapy (p < 0.05) in PM/DM patients. Tacrolimus treatment significantly attenuated TREC content within cultured CD4+CD8- cells from PM/DMpatients (p < 0.05), but total cell counts were not significantly changed. These results indicate that tacrolimus therapy suppresses not only activated T-lymphocytes, but also some naïve T-cell subsets in both PM and DM.

[A new rehabilitation strategy for patients with Parkinson disease: a proposal of mentality-orientated rehabilitation].

Rehabilitation, a treatment strategy that involves group effort with multiple specialists, roles, and facilities, is widely offered to patients in need. The current rehabilitation strategy is mainly disability oriented, and, in principle, starts from the evaluation of motor function and aims to strengthen the deteriorated function/s. Therefore, this method is very effective for patients with acute diseases. However, the effect of such a rehabilitation strategy on gradually progressive neurodegenerative diseases is not well clarified. In particular, Disability-oriented Rehabilitation has not shown an adequate effect in Parkinson disease, which is associated with psychological stress. In this report, we provide an outline of a new rehabilitation strategy and introduce Mentality-oriented Rehabilitation for patients with Parkinson disease.

Anti-neuronal antibodies in acute pandysautonomia.

We encountered two patients with acute pandysautonomia who subacutely exhibited extensive autonomic dysfunction after antecedent infections. Although these patients had been suffering from autonomic disturbance for several months, they both had a good clinical course after plasma exchange and intravenous immunoglobulin therapy. Thin-layer chromatography (TLC)-immunostaining did not demonstrate any antibodies against gangliosides, but immunoblot analysis showed antibodies against a neuroblastoma cell line, SH-SY5Y, in serum samples. Furthermore, ganglionic acetylcholine receptor autoantibodies were detected in one patient. These findings suggest that neuronal antibodies against the autonomic nervous system play an important role in the pathogenesis of acute pandysautonomia.