Hidehiro Mizusawa

Objectives Clinical and pathological significance of gadolinium (Gd)‐enhancing pattern on magnetic resonance imaging (MRI), including ring enhancement (RE), is well documented in multiple sclerosis but not in neuromyelitis optica (NMO), especially in the spinal cord. The purpose of this study is to examine the prevalence of spinal cord RE in NMO and to determine the association between clinical characteristics and spinal cord RE. Materials and methods We retrospectively examined Gd‐enhanced spinal cord MRI scans, during the acute phase, in patients with anti‐aquaporin 4‐positive NMO, including NMO spectrum disorder. We then analysed their clinical features and MRI imaging characteristics of spinal cord lesions. Results Of the 30 patients with NMO, we enrolled 12 patients with 16 Gd‐enhanced spinal cord MRI scans in this study. Five scans revealed RE (31.2%). Male ratio, as well as myelin basic protein (MBP) levels, in the cerebrospinal fluid (CSF) of patients with RE was significantly higher than those of patients without RE (P = 0.018, P = 0.026, respectively). Conclusions Spinal cord RE is common in patients with NMO. Higher MBP levels in the CSF of patients with RE can be associated with a higher degree of myelin damage.

Background: There is considerable interest in inducing RNA interference (RNAi) in neurons to study gene function and identify new targets for disease intervention. Although short interfering RNAs (siRNAs) have been used to silence genes in neurons, in vivo delivery of RNAi remains a major challenge, especially by systemic administration. We have developed a highly efficient method for in vivo gene silencing in dorsal root ganglia (DRG) by using short hairpin RNA-expressing single-stranded adeno-associated virus 9 (ssAAV9-shRNA). Results: Intraperitoneal administration of ssAAV9-shRNA to neonatal mice resulted in highly effective and specific silencing of a target gene in DRG. We observed an approximately 80% reduction in target mRNA in the DRG, and 74.7% suppression of the protein was confirmed by Western blot analysis. There were no major side effects, and the suppression effect lasted for more than three months after the injection of ssAAV9-shRNA. Conclusions: Although we previously showed substantial inhibition of target gene expression in DRG via intrathecal ssAAV9-shRNA administration, here we succeeded in inhibiting target gene expression in DRG neurons via intraperitoneal injection of ssAAV9-shRNA. AAV9-mediated delivery of shRNA will pave the way for creating animal models for investigating the molecular biology of the mechanisms of pain and sensory ganglionopathies.

Progressive multifocal leukoencephalopathy (PML), a rare but fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. As PML develops in individuals with various underlying disorders sporadically and infrequently, a nationwide survey of PML is difficult. This study was conducted to elucidate the characteristics of PML in Japan through an internet-assisted laboratory surveillance program.

The majority of cases of anti-glutamic acid decarboxylase (GAD)-antibody-positive cerebellar ataxia are reported to have high levels of anti-GAD antibody, and the diagnostic value of low titers of anti-GAD antibody in a patient with cerebellar ataxia is still unknown. The purpose of this study was to verify the characteristics of low-titer-anti-GAD-antibody-positive cerebellar ataxia patients and the diagnostic value of low titers of anti-GAD antibody in patients with cerebellar ataxia. The subjects were six patients positive for low-titer GAD antibody (1.0. Two of the six patients were thyroid antibody-positive, and one was both antinuclear- and anti-SS-A antibody-positive. After the administration of immunotherapy to three patients, two showed clear effectiveness, and one, transient effectiveness. Effectiveness was greatest in the two patients with familial occurrence of the disease. In cerebellar ataxia, regardless of family history or isolated illness, it is critical to measure the GAD antibody level, and, even with a low titer level, if the result is positive, immunotherapy should be considered.

Schwann cells exhibit a high degree of plasticity in adult peripheral nerves after mechanical injury; they have, therefore, been implicated in promoting nerve regeneration. However, Schwann cell behavior after ischemic injury has not yet been elucidated. To determine how Schwann cell plasticity may contribute to recovery from ischemic neuropathy, we used a rat model in which ischemia was induced in the tibial nerve by a 5-hour occlusion of the supplying arteries. Proliferation of immature Schwann cells that emerged in the injured nerve was evaluated by double immunostaining for the p75 neurotrophin receptor and proliferating cell nuclear antigen. The number of proliferating cell nuclear antigen/p75 neurotrophin receptor double-positive cells increased significantly in 1 to 2 weeks after ischemia and subsequently decreased by 4 weeks. During this time, the postmitotic Schwann cells differentiated into mature cells, as demonstrated with bromodeoxyuridine incorporation, which facilitated axon guidance and subsequent axon remyelination. These results suggest the emergence and proliferation of immature Schwann cells that contribute to nerve regeneration after ischemic injury. The manipulation of this population of proliferating immature Schwann cells may be a useful strategy for treating ischemic peripheral neuropathy.

Introduction: Polymyositis (PM) and dermatomyositis (DM) are chronic inflammatory muscle diseases, in which chemokines are thought to contribute to inflammatory cell migration into muscle. In this study, we retrospectively analyzed the expressions of CX3CL1/fractalkine and its corresponding receptor, CX3CR1, in muscle and lung with interstitial lung disease (ILD) of PM patients and DM patients, and determined the correlation between serum soluble CX3CL1 level and disease activity. Methods: Expressions of CX3CL1 and CX3CR1 in muscle and lung tissue were analyzed by immunohistochemistry. Serum CX3CL1 concentrations were measured by ELISA. For evaluation of patients' disease activity, serum creatinine kinase, manual muscle testing, and the alveolar-arterial oxygen pressure difference were used independently. Results: CX3CL1 was expressed on infiltrated mononuclear cells and endothelial cells in muscle affected by PM and DM and in lung with ILD, whereas CX3CR1 was expressed on some CD4⁺ T cells, a majority of CD8⁺ T cells, and most macrophages in muscle, and on infiltrated mononuclear cells in the lung. Serum soluble CX3CL1 was significantly higher in PM patients and DM patients than in healthy controls. The CX3CL1 level was correlated with serum creatinine kinase and manual muscle testing score. In patients with PM and DM with ILD, serum CX3CL1 was also correlated with alveolar-arterial oxygen pressure difference. Furthermore, CX3CL1 was significantly decreased after conventional treatment. Conclusions: The interaction between CX3CL1 and CX3CR1 might contribute to the inflammatory cell infiltration into affected muscle and lung with ILD in PM patients and DM patients. Serum CX3CL1 level could be a surrogate marker of disease activity.

Transplantation of human neural stem/progenitor cells (hNSPCs) is a promising method to regenerate tissue from damage and recover function in various neurological diseases including brain ischemia. Galectin-1(Gal1) is a lectin that is expressed in damaged brain areas after ischemia. Here, we characterized the detailed Gal1 expression pattern in an animal model of brain ischemia. After brain ischemia, Gal1 was expressed in reactive astrocytes within and around the infarcted region, and its expression diminished over time. Previously, we showed that infusion of human Gal1 protein (hGal1) resulted in functional recovery after brain ischemia but failed to reduce the volume of the ischemic region. This prompted us to examine whether the combination of hNSPCs-transplantation and stable delivery of hGal1 around the ischemic region could reduce the ischemic volume and promote better functional recovery after brain ischemia. In this study, we transplanted hNSPCs that stably overexpressed hGal1 (hGal1-hNSPCs) in a model of unilateral focal brain ischemia using Mongolian gerbils. Indeed, we found that transplantation of hGal1-hNSPCs both reduced the ischemic volume and improved deficits in motor function after brain ischemia to a greater extent than the transplantation of hNSPCs alone. This study provides evidence for a potential application of hGal1 with hNSPCs-transplantation in the treatment of brain ischemia.

BACKGROUND AND PURPOSE: Previous neuropathologic studies in chronic hydrocephalus have suggested the presence of white matter damage, presumably from mechanical pressure due to ventricular enlargement and metabolic derangement. This study aimed to investigate the diffusional properties of the CST in patients with iNPH by using DTI and to determine whether this method could be used as a new diagnostic tool to differentiate patients with iNPH from those with AD and PDD and control subjects. MATERIALS AND METHODS: We enrolled 18 patients with iNPH, 11 patients with AD, 11 patients with PDD, and 19 healthy control subjects. Diffusion tensor metrics of the segmented CST, including FA values, axial eigenvalues, and radial eigenvalues, were evaluated by using tract-specific analysis. The anisotropy color-coding tractography of the CST was visually evaluated. The DTI findings were compared among groups. RESULTS: Tract-specific analysis of the CST showed that FA values and axial eigenvalues were significantly increased (P < .001), whereas radial eigenvalues were not significantly altered, in patients with iNPH compared with other subjects. The CST tractographic images in patients with iNPH was visually different from those in other subjects (P < .001). In discriminating patients with iNPH from other subjects, the CST FA values had a sensitivity of 94% and specificity of 80% at a cutoff value of 0.59. CONCLUSIONS: Our results suggest that patients with iNPH have altered microstructures in the CST. Quantitative and visual CST evaluation by using DTI may be useful for differentiating patients with iNPH from patients with AD or PDD or healthy subjects.

Patients with Parkinson's disease (PD) can develop mild cognitive impairment (PD‐MCI), frequently progressing to dementia (PDD). Here, we aimed to elucidate the relationship between white matter alteration and cognitive status in PD and dementia with Lewy bodies (DLB) by using diffusion tensor imaging. We also compared the progression patterns of white and gray matter and the cerebral perfusion. We enrolled patients with PD cognitively normal (PD‐CogNL, n = 32), PD‐MCI (n = 28), PDD (n = 25), DLB (n = 29), and age‐ and sex‐matched healthy control subjects (n = 40). Fractional anisotropy (FA) map of a patient group was compared with that of control subjects by using tract‐based spatial statistics. For the patient cohort, intersubject voxel‐wise correlation was performed between FA values and Mini‐Mental Status Examination (MMSE) scores. We also evaluated the gray matter and the cerebral perfusion by conducting a voxel‐based analysis. There were significantly decreased FA values in many major tracts in patients with PD‐MCI, PDD, and DLB, but not in PD‐CogNL, compared with control subjects. FA values in the certain white matter areas, particularly the bilateral parietal white matter, were significantly correlated with MMSE scores in patients with PD. Patients with PDD and DLB had diffuse gray matter atrophy. All patient groups had occipital and posterior parietal hypoperfusion when compared with control subjects. Our results suggest that white matter damage underlies cognitive impairment in PD, and cognitive impairment in PD progresses with functional alteration (hypoperfusion) followed by structural alterations in which white matter alteration precedes gray matter atrophy. Hum Brain Mapp, 2011.