Tsugio Akutsu

RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis

In multiple sclerosis, activated CD4+ T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow–derived dendritic cells (BMDCs) and that CD4+ T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4+ T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4+ T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.

Significance of the Hemorrhagic Site for Recurrent Bleeding: Prespecified Analysis in the Japan Adult Moyamoya Trial

Background and Purpose— The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. Methods— The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. Results— Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01–0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39–6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60–21.27). Conclusions— Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

Biphasic neurovascular changes in prolonged migraine aura in familial hemiplegic migraine type 2

Objective To report biphasic changes in cerebral blood flow (CBF) in the acute phase of hemiplegic migraine with prolonged aura (HMPA), in which aura symptoms lasted longer than 24 h, in three patients with familial hemiplegic migraine (FHM) carrying a p.H916L mutation in ATP1A2 gene. Methods We assessed neurovascular changes with time in the affected cerebral hemisphere corresponding to aura symptoms during the acute phase of HMPA. Arterial spin labelling MRI, SPECT for CBF measurement and EEG in three attacks, in one attack FDG-PET measurement for cerebral metabolism was performed. We evaluated CBF at different phases of aura symptoms in 11 attacks of HMPA. Results In two attacks, we found biphasic CBF changes beginning with hypoperfusion followed by persistent hyperperfusion. FDG-PET revealed increased cerebral glucose metabolism in the regions corresponding to hyperperfusion on day 4 when aura symptoms still persisted. In four attacks, Z-score-based CBF mapping revealed multifocal hypoperfusion in the early phase. Hypoperfusion in our study was seen within 19 h of the onset of the symptoms in five of seven attacks, while hyperperfusion was seen 18 h or later in eight of nine attacks. EEG showed attenuated alpha activity without paroxysmal discharge. Conclusions This is the first report showing biphasic CBF changes during the prolonged aura of FHM2. This study suggested that the results of cross-sectional CBF studies should be interpreted carefully. Initial multifocal hypoperfusion is likely due to functional depression of multifocal origin in the affected hemisphere, but the mechanism of persistent hyperperfusion requires further investigation.

Coexistence of Charcot–Marie–Tooth disease type 1A and chronic inflammatory demyelinating polyradiculoneuropathy with conduction blocks

We present a 47‐year‐old woman with upper extremity muscle weakness and sensory disturbance during a slowly progressive course of leg muscle weakness. First, she was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy. However, with gene analysis of PMP22 duplication, she was diagnosed with Charcot–Marie–Tooth type 1A. In the electrophysiological study, nerve conduction blocks were shown, which is inconsistent with Charcot–Marie–Tooth type 1A. Intravenous immunoglobulin therapy improved both her symptoms and the conduction blocks. We suggest that inflammatory demyelinating polyradiculoneuropathy was associated with Charcot–Marie–Tooth type 1A in this patient. The presence of the conduction blocks could be a hallmark of the associating inflammatory demyelinating polyradiculoneuropathy. Intravenous immunoglobulin therapy might be partly effective in such patients.