桑原 聡

Objective: Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K&lt sup&gt +&lt /sup&gt channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. Methods: Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. Results: Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses) excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K&lt sup&gt +&lt /sup&gt current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. Conclusions: This study showed that patients with CFS might have abnormal kinetics in a slow K&lt sup&gt +&lt /sup&gt current. Significance: Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K&lt sup&gt +&lt /sup&gt channel openers.

Thymectomy is an effective treatment for myasthenia gravis (MG). However, there is limited data on its effectiveness in non-thymomatous late-onset MG (LOMG). The aim of this study was to analyze the effects of thymectomy in LOMG. We retrospectively reviewed the 2-year post-thymectomy prognosis in 39 consecutive patients with non-thymomatous, anti-acetylcholine receptor antibody positive, and generalized LOMG (age at onset a parts per thousand yen50 years). The MG foundation of America (MGFA) classification, MGFA post-intervention status, dosage of prednisolone and pyridostigmine, and anti-acetylcholine receptor antibody titers were evaluated. Among the 39 LOMG patients, thymic hyperplasia was seen in 5 (12.8 %). MGFA classification and prednisolone dosage before thymectomy were similar between the LOMG with thymic hyperplasia group (n = 5) and the LOMG with involuted thymus group (n = 34). Two years after thymectomy, the LOMG patients with thymic hyperplasia showed higher proportion of remission (60 vs. 26 %) and received lower prednisolone dosage compared to patients with involuted thymus (0.8 vs. 4.0 mg/day). Notably, the proportion of patients with minimal manifestation or better status with receiving a parts per thousand currency sign5 mg/day prednisolone was much higher in the thymic hyperplasia group than in the involuted thymus group (100 vs. 62 %). In conclusion, thymectomy could have beneficial effects in generalized LOMG, particularly in patients with thymic hyperplasia.

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

To study distribution and patterns of nerve hypertrophy in chronic inflammatory demyelinating polyneuropathy (CIDP), magnetic resonance neurography with 3-dimensional reconstruction of short tau inversion recovery images was performed in 33 patients. This technique clearly showed longitudinal morphological changes from the cervical roots to the nerve trunks in the proximal arm. Nerve enlargement was detected in 88% of the patients. According to the clinical subtype of CIDP, typical CIDP patients showed symmetric and root-dominant hypertrophy, whereas Lewis-Sumner syndrome patients had multifocal fusiform hypertrophy in the nerve trunks. The patterns of nerve hypertrophy presumably reflect the different pathophysiology of each CIDP subtype. Ann Neurol 2014.

Objective: To identify useful MRI abnormalities in the putamen for diagnosing multiple system atrophy. Methods: Patients with multiple system atrophy (n = 15), Parkinson's disease (n = 16), or progressive supranuclear palsy (n = 9) and healthy controls (n = 10) were enrolled. Using a visual analog scale, 4 examiners independently rated high-intensity signals along the lateral putamen on T2-weighted and T2*-weighted images, low-intensity signals within the putamen on T2-weighted and T2*-weighted images, and putaminal atrophy. Receiver operating characteristic analyses were performed, and the area under the receiver operating characteristic curve was calculated. Results: For differentiating multiple system atrophy from progressive supranuclear palsy, Parkinson's disease, and healthy controls, the mean area under the curve values was the highest for low-intensity signals within the putamen on T2*-weighted images (0.797, 0.867, 0.896, respectively). Variations in the area under the curve values among the 4 examiners were the smallest in low-intensity signals within the putamen on T2*-weighted images. Good inter-rater reliability was achieved for low-intensity signals within the putamen on T2*-weighted images and high-intensity signals along the lateral putamen on T2*-weighted images. Conclusion: Low-intensity signals within the putamen on T2*-weighted images is the most useful MRI abnormality for diagnosing multiple system atrophy. (C) 2015 Elsevier B.V. All rights reserved.

To identify serum cytokine networks specific to chronic inflammatory demyelinating polyneuropathy (CIDP), serum samples of two subgroups (18 patients with typical CIDP and 12 patients with multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]) were analyzed with multiplex magnetic bead-based cytokine assay. TNF-alpha, HGF, MIP-1 beta and IL-1 beta levels were significantly higher in total CIDP patients than in normal controls. Of these, HGF levels were elevated in typical CIDP patients, but not in MADSAM patients. Patients with high HGF levels showed good responses to steroid treatment. Different cytokine profiles among the CIDP subtypes presumably reflect differences in pathophysiology. (C) 2014 Elsevier B.V. All rights reserved.

Background and objectivesSeveral symptoms and signs are characteristic of multiple sclerosis (MS) such as Lhermitte's sign, Uhthoff's phenomenon and painful tonic seizure. Neuromyelitis optica (NMO) is another inflammatory disease of the central nervous system, and most of the opticospinal form of MS is thought to be NMO. This study aimed to investigate the frequencies of symptoms and signs, previously regarded as characteristic of MS, in NMO and MS patients. MethodsConsecutive Japanese NMO-plus patients [NMO (n=30) or partial NMO (n=18)] and MS patients (n=128) seen at Chiba University Hospital between 2011 and 2012 were investigated for the frequencies of symptoms and signs characteristic of MS. Logistic regression analyses were used to identify factors that distinguished NMO-plus from MS. ResultsUnivariate analyses revealed that tonic seizures, Lhermitte's sign, persistent pain, fatigue and girdle sensation were more frequent in NMO-plus patients than in MS patients. Multivariate logistic regression analysis showed that paroxysmal itching, Uhthoff's phenomenon, Lhermitte's sign and girdle sensation were more characteristic of NMO-plus than of MS. ConclusionsSeveral classical MS symptoms and signs are more frequent in NMO patients than MS patients, which may be caused by the differences in the severity of inflammation, and localization and extensiveness of demyelinated lesions.

Neuronal or axonal ion channel function can be impaired or altered in a number of disorders, such as acquired (autoantibody-mediated, toxic, and metabolic) and genetic channelopathies, and even neurodegenerative (motor neuron disease) or inflammatory diseases (multiple sclerosis, immune-mediated neuropathies). When specific channels are affected, axonal/neuronal excitability primarily alters according to original function of the corresponding channels. Separately, in the 1990s, axonal excitability testing was developed to assess ion channel function, membrane potential, and passive membrane properties non-invasively in human subjects. Using this technique, numerous papers on altered axonal excitability in a variety of disorders have been published since 2000. In a recent issue of Experimental Neurology, Park et al. demonstrated changes in peripheral axonal excitability in limbic encephalitis and acquired neuromyotonia with anti-voltage gated potassium channel antibodies. Unexpectedly, the results were not consistent with those caused by simple potassium channel blockade, suggesting that multiple other factors contribute to altered axonal excitability. In contrast it was reported that patients with episodic ataxia type 1 (genetic channelopathy with mutation of Kv1.1 channel gene) show prominent excitability changes exactly compatible with fast potassium channel blockade. This commentary aims to highlight findings of this study in a broader context, and provides possible explanations for the discrepancy of patterns of axonal excitability changes in acquired and genetic potassium channelopathies. (C) 2014 Elsevier Inc. All rights reserved.

Introduction: Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently, the prognosis of POEMS was substantially improved by introduction of therapeutic intervention for myeloma. However, no randomised clinical trial has been performed because of the rarity and severity of the disease. Methods and analysis: The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome, with an additional 48-week open-label safety study. Adults with POEMS syndrome who have no indication for transplantation are assessed for eligibility at 12 tertiary neurology centres in Japan. Patients who satisfy the eligibility criteria are randomised (1:1) to receive thalidomide (100-300 mg daily) plus dexamethasone (12 mg/m(2) on days 1-4 of a 28-day cycle) or placebo plus dexamethasone. Both treatments were administered for 24 weeks (six cycles; randomised comparative study period). Patients who complete the randomised study period or show subacute deterioration during the randomised period participate in the subsequent 48-week open-label safety study (long-term safety period). The primary end point of the study is the reduction rate of serum VEGF levels at 24 weeks. Ethics and dissemination: The protocol was approved by the Institutional Review Board of each hospital. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, Japan (No. 22-1716). The J-POST Trial is currently ongoing and is due to finish in August 2015. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations and will also be disseminated to participants.

Lymphomatoid granulomatosis (LYG) is an angiocentric and angiodestructive lymphoproliferative disease involving extranodal sites. Although LYG cerebral lesions are usually located adjacent to LYG pulmonary lesions, few reports have described the occurrence of primary cerebral LYG. We herein discuss a case of a 40-year-old Japanese woman with primary cerebral LYG that caused various neurological symptoms for more than five years and progressed to methotrexate-associated lymphoproliferative disease under treatment with immunosuppressive therapy. This case suggests that primary cerebral LYG should be considered a lymphoid neoplasm manifesting as a primary brain tumor and a component of the differential diagnosis of chronic neuroinflammatory disorders.

Myeloid sarcoma is a rare hematological disorder that presents as an extramedullary mass of immature myeloid precursors. We herein present the case of a 57-year-old man with a seven-month history of progressive weakness in the right upper extremity. Reconstruction magnetic resonance neurography showed a marked enlargement of the right brachial plexus. Fluorodeoxyglucose positron emission tomography revealed a radioactive lesion in the sacrum, in addition to the right brachial plexus, and a biopsy of the sacrum revealed myeloid sarcoma. The brachial plexus lesion was also regarded as myeloid sarcoma because of the treatment response. Isolated myeloid sarcoma involving the brachial plexus is very rare and its diagnosis is difficult as there was neither a history of leukemia nor bone marrow involvement in this patient. In this case, reconstructed magnetic resonance neurography was useful for detecting the brachial plexus mass lesion which led to an early diagnosis and good recovery.

Introduction. Patients with Parkinson's disease (PD) showed reduced myocardial I-123-MIBG uptake, which may affect autonomic regulation. We investigated correlation between MIBC accumulation and cardiovascular autonomic function in PD. Methods. We performed myocardial MIBG scintigraphy, heart rate variability (HRV) analysis, and the head-up tilt test (HUT) in 50 PD patients (66.4 +/- 7.8 years; duration 5.5 +/- 5.9 years). Autonomic function tests were also performed in 50 healthy controls (66.5 +/- 8.9 years). As HRV parameters, a high-frequency power (HF, 0.15-0.4Hz), a low-frequency power (LF, 0.04-0.15Hz), and LF/HF ratio were used. Results. Our PD patients had a significant reduction in LF and HF compared with the controls (P = 0.005 and P = 0.01). In HUT, systolic and diastolic blood pressure falls in the PD group were significantly greater than those in the controls (P = 0.02 and P = 0.02). The washout rate of MIBG was negatively correlated with blood pressure changes during HUT. Conclusion. Our PD patients showed reduced HRV, blood pressure dysregulation, and reduced MIBG accumulation, which was correlated with blood pressure dysregulation. Orthostatic hypotension in PD may be mainly caused by sympathetic postganglionic degeneration.

Introduction. Patients with Parkinson's disease (PD) showed reduced myocardial 123I-MIBG uptake, which may affect autonomic regulation. We investigated correlation between MIBC accumulation and cardiovascular autonomic function in PD. Methods. We performed myocardial MIBG scintigraphy, heart rate variability (HRV) analysis, and the head-up tilt test (HUT) in 50 PD patients (66.4±7.8 years duration 5.5±5.9 years). Autonomic function tests were also performed in 50 healthy controls (66.5±8.9 years). As HRV parameters, a high-frequency power (HF, 0.15-0.4 Hz), a low-frequency power (LF, 0.04-0.15 Hz), and LF/HF ratio were used. Results. Our PD patients had a significant reduction in LF and HF compared with the controls (P=0.005 and P=0.01). In HUT, systolic and diastolic blood pressure falls in the PD group were significantly greater than those in the controls (P=0.02 and P=0.02). The washout rate of MIBG was negatively correlated with blood pressure changes during HUT. Conclusion. Our PD patients showed reduced HRV, blood pressure dysregulation, and reduced MIBG accumulation, which was correlated with blood pressure dysregulation. Orthostatic hypotension in PD may be mainly caused by sympathetic postganglionic degeneration.

Objective: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare multisystem disease characterised by plasma cell dyscrasia and overproduction of vascular endothelial growth factor (VEGF). VEGF is assumed to be useful in monitoring disease activity, because VEGF levels usually decrease after treatment. However, there is no study to investigate whether the extent of decrease in VEGF correlates with clinical outcome. We tested the predictive efficacy of serum VEGF levels in POEMS syndrome. Method: This was an institutional review board approved retrospective observational cohort study of 20 patients with POEMS monitored regularly for more than 12 months (median follow-up, 87 months) after treatment onset using our prospectively accumulated database of POEMS from 1999 to 2015. Patients were treated by autologous peripheral blood stem cell transplantation or thalidomide administration. Serum VEGF was measured by ELISA. Outcome measures included clinical and laboratory findings and relapse-free survival. Results: Serum VEGF levels decreased rapidly after treatment, and stabilised by 6 months post treatment. Patients with normalised serum VEGF levels (<1040 pg/mL) at 6 months showed prolonged relapse-free survival (HR=12.81, 95% CI 2.691 to 90.96; p=0.0001) and greater later clinical improvement. The rate of serum VEGF reduction over the first 6 months post treatment correlated with increased grip strength, serum albumin levels, and compound muscle action potential amplitudes at 12 months. Conclusions: Serum VEGF level at 6 months post treatment is a predicative biomarker for disease activity and prognosis in POEMS syndrome. Serum VEGF could be used as a surrogate endpoint for relapse-free survival or clinical or laboratory improvement of POEMS syndrome for clinical trials.

The number of patients with Alzheimer's disease (AD) is increasing worldwide, and available drugs have shown limited efficacy. Hence, preventive interventions and treatments for presymptomatic AD are currently considered very important. Obesity rates have also been increasing dramatically and it is an independent risk factor of AD. Therefore, for the prevention of AD, it is important to elucidate the pathomechanism between obesity and AD. We generated high calorie diet (HCD)-induced obese tauopathy model mice (PS19), which showed hyperleptinemia but limited insulin resistance. HCD enhanced tau pathology and glial activation. Conversely, voluntary exercise with a running wheel normalized the serum leptin concentration without reducing body weight, and restored the pathological changes induced by HCD. Thus, we speculated that persistent hyperleptinemia played an important role in accelerating pathological changes in PS19 mice. Leptin primarily regulates food intake and body weight via leptin receptor b (LepRb). Interestingly, the nuclear staining for p-STAT3, which was activated by LepRb, was decreased in hippocampal neurons in HCD PS19 mice, indicating leptin resistance. Meanwhile, astroglial activation and the astrocytic expression of a short LepR isoform, LepRa, were enhanced in the hippocampus of HCD PS19 mice. Real-time PCR analysis demonstrated that leptin increased mRNA levels for pro-inflammatory cytokines including IL-1 beta and TNF-alpha in primary cultured astrocytes from wild type and LepRb-deficient mice. These observations suggest that persistent hyperleptinemia caused by obesity induces astrocytic activation, astrocytic leptin hypersensitivity with enhanced LepRa expression, and enhanced inflammation, consequently accelerating tau pathology in PS19 mice. (C) 2014 The Authors. Published by Elsevier Inc.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Bradykinin is the end-product of the kallikrein/kinin system, which has been recognized as an endogenous target for combating CNS inflammation. Angiotensin-converting enzyme (ACE) inhibitors influence the kallikrein/kinin system and reportedly have immunomodulatory characteristics. The objectives of this study were to determine whether bradykinin is involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and whether bradykinin control by the ACE inhibitor could be a therapeutic target in MS. The ACE inhibitor enalapril (1.0 or 0.2 mg/kg/day) was administered orally to EAE mice and the serum levels of bradykinin and cytokines in EAE mice were analysed. As a result, the administration of enalapril increased serum bradykinin levels, decreased the clinical and pathological severity of EAE and attenuated interleukin-17-positive cell invasion into the CNS. Additionally, bradykinin receptor antagonist administration reduced the favourable effects of enalapril. Our results suggest that bradykinin is involved in the pathomechanism underlying CNS inflammation in EAE, possibly through inhibiting cell migration into CNS. Control of the kallikrein/kinin system using ACE inhibitors could be a potential therapeutic strategy in MS.

Purpose:In current electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy, the cutoff values of distal compound muscle action potential (DCMAP) duration are defined using electromyogram low-cut filter setting of 20 Hz. We aimed to assess effects of low-cut filter on DCMAP duration (10 vs. 20 Hz).Methods:We prospectively measured DCMAP duration in 130 normal controls and 42 patients, fulfilling diagnostic criteria for typical chronic inflammatory demyelinating polyneuropathy by European Federation of Neurological Societies/Peripheral Nerve Society.Results:Distal compound muscle action potential duration was significantly shortened with 20-Hz than 10-Hz filtering. When the cutoff values were defined as the upper limit of normal (ULN, mean + 2.5SD), the sensitivity/specificity was 67%/95% in 10-Hz recordings, and 69%/95% in 20-Hz recordings. This diagnostic accuracy was similar to that defined by receiver operating characteristic analyses.Conclusions:Distal compound muscle action potential duration significantly affected by the low-cut electromyogram filter setting, but with at least 10 and 20 Hz, the diagnostic accuracy is similar.

We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.

Background: Bacterial meningitis is a neurological emergency. Early diagnosis and rapid initiation of antimicrobial therapy are vital. Methods: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is increasingly used as a rapid and accurate microbial diagnostic method for species identification of pathogens. Although this technology requires a growth step to obtain bacterial colonies for the acquisition of substantial spectra in most cases, it can also be used to analyze clinical specimens such as urine and cerebrospinal fluid for direct bacterial identification. There are very few reports describing the use of MALDI-TOF MS for the direct detection of microorganisms causing bacterial meningitis. Results: We describe a case of bacterial meningitis caused by Klebsiella pneumoniae in which MALDI-TOF MS provided a rapid bacteriological diagnosis, thus enabling early and appropriate treatment. Conclusions: Identification of microbes based on MALDI-TOF MS is now an important technology in clinical microbiology laboratories that are required to provide a rapid diagnosis of bacterial meningitis. (C) 2014 Elsevier B.V. All rights reserved.

Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is currently classified into clinical subtypes, including typical and atypical forms (multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and distal acquired demyelinating symmetric neuropathy (DADS)). The aim of this study was to elucidate the patterns and severity of breakdown of the blood-nerve barrier (BNB) in each CIDP subtype. Methods: We evaluated the effects of sera obtained from patients with typical CIDP, MADSAM and DADS and control subjects on the expression levels of tight junction proteins and transendothelial electrical resistance (TEER) value in human peripheral nerve microvascular endothelial cells (PnMECs). Results: The sera obtained from the patients with the three clinical phenotypes of CIDP decreased the amount of claudin-5 protein levels and TEER values in the PnMECs. In addition, the sera obtained from typical CIDP patients more prominently reduced claudin-5 protein levels and TEER values in the PnMECs than did that obtained from the MADSAM and DADS patients. Furthermore, the severity of BNB disruption after exposure to the sera was associated with higher Hughes grade, lower MRC score, more pronounced slowing of motor nerve conduction in the median nerve and higher frequency of abnormal temporal dispersion. Conclusions: Sera derived from typical CIDP patients destroy the BNB more severely than those from MADSAM or DADS patients. The extent of BNB disruption in the setting of CIDP is associated with clinical disability and demyelination in the nerve trunk. These observations may explain the phenotypical differences between CIDP subtypes.

Background: Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression. Methods: Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits. Results: Forty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 +/- 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease. Conclusions: Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 +/- 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.

Aims Because time-dependent changes and gender differences in urinary dysfunction in patients with multiple system atrophy (MSA) are yet unknown, we aimed to determine these parameters through a combination of urodynamic examination and the results of a questionnaire on urinary symptoms. Methods We retrospectively reviewed 66 patients with MSA who responded to a urinary symptoms questionnaire and underwent urodynamic examination more than twice. The participants' mean age was 62 years and mean disease duration at the first urodynamic examination was 3.2 years. Mean duration between the first and second urodynamic examination was 441 days. Results With regard to overall (both genders) time-dependent change, none of the urinary symptoms showed significant differences. In the urodynamic examination there were significant differences in reduced urine flow, increased post-void residuals, and decreased detrusor contractility at the second examination. With regard to gender differences, at the first examination, night-time urinary frequency, and voiding symptoms were significantly more severe in male than in female patients; however, at the second examination, except for urinary urgency, gender differences were not observed for any other symptoms. In urodynamic examination, the degree of detrusor contraction was significantly less in male patients at the first examination. However, no significant differences were found in urodynamic examination at the second examination. Conclusions The present study indicates that voiding dysfunction progressed without significant worsening of voiding symptoms. In addition, gender differences are important in evaluating urinary dysfunction being basically less severe in female than in male patients, at least during the early stage. Neurourol. Urodynam. 33:516-523, 2014. (c) 2013 Wiley Periodicals, Inc.

Rho is a small molecular weight GTP-binding protein and works as a molecular shuttling switch between an active (GTP-bound) and inactive (GDP-bound) state. Rho is known to be involved in cell motility, cell adhesion, and cytokinesis through actin cytoskeleton reorganization. The GTP-bound form of Rho interacts with its specific downstream target, triggering intracellular signaling cascades. Rho effectors such as Rho-kinases have been isolated on the basis of their selective binding to the GTP-bound form of Rho. Rho-kinase is thought to have an important role in the pathogenesis of a variety of neurological diseases because activation of the Rho/Rho-kinase pathway has been observed in various central nervous system disorders. Previous histochemical studies have shown multiple molecular mechanisms for the regulation of Rho-kinase. Neuroimaging of Rho/Rho-kinase has rarely been studied because of a lack of appropriate radiotracers. Recently, N-[C-11]methyl-hydroxyfasudil, a new radiotracer for positron emission tomography (PET), has been introduced to measure Rho-kinase activity. In this study, the regional distribution and kinetics of N-[C-11]methyl-hydroxyfasudil were investigated in the brains of mice. A 90-min dynamic scan was performed following intravenous infusion of N-[C-11]methyl-hydroxyfasudil. The uptake of N-[C-11]methyl-hydroxyfasudil reached a maximum within 5 min and gradually decreased in all organs. The standard uptake values (SUVs) in the brain, liver, and kidney on average between 30 to 60 min were 0.17 +/- 0.03, 0.76 +/- 0.18, and 0.62 +/- 0.18 and from 60 to 90 min were 0.15 +/- 0.01, 0.69 +/- 0.33, and 0.64 +/- 0.17, respectively. N-[C-11]Methyl-hydroxyfasudil showed a widespread distribution throughout the brain, with low levels of radioactivity. Radioactivity concentration in plasma at 90 min after injection of N-[C-11]methyl-hydroxyfasudil resulted in SUVs in the control and fasudil pretreatment of 0.0013 and 0.0023 +/- 0.0008, respectively. Compared to normal control mice, about twofold higher radioactivity concentration was observed in fasudil-pretreated mice. In a cold brain injury mouse model, accumulation of N-[C-11]methyl-hydroxyfasudil was slightly higher at the injury site than that at the control site, and the difference was statistically significant in the "24 h after injury" group (P < 0.05). These results suggest that following brain injury, N-[C-11]methyl-hydroxyfasudil binds to the active form of Rho-kinase. PET imaging using N-[C-11]methyl-hydroxyfasudil could provide new insights into the pathophysiology of a variety of neurological disorders including stroke, inflammatory diseases, demyelinating diseases, Alzheimer's disease, and neuropathic pain.

Accumulating evidence indicates that obesity is an independent risk factor for developing Alzheimer disease (AD). Recent studies have shown that diet-induced obesity (DIO) enhances AD-related pathologies in transgenic mouse models of the disease. DIO increases amyloid beta (A beta) deposition in amyloidogenic transgenic mice and enhances tau phosphorylation in tau transgenic mice. However, it remains unclear whether DIO also enhances AD-related pathological processes in wild-type (WT) mice. In this study, we examined the effects of DIO on A beta and tau pathology in WT mice using immunohistochemistry. In addition, we evaluated the protective effect of voluntary exercise on the DIO-induced pathological changes. DIO caused tau phosphorylation and astroglial activation in the hippocampus in WT mice. Interestingly, these changes were associated with enhanced astrocytic leptin receptor (LepR) expression and mild microgliosis, but not A beta accumulation. Although phosphorylated tau staining was only observed in the hippocampus, astrogliosis and microgliosis were present in both the amygdala and hippocampus. However, no apparent neuronal loss was observed. Voluntary exercise prevented these DIO-induced pathological changes. Our results demonstrate for the first time that DIO causes tau phosphorylation and that astrocytic LepR might be involved in the pathological process in WT mouse hippocampus. Our findings also suggest that physical exercise is a promising strategy for the prevention of AD in patients with obesity. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.