Fumiharu Kimura

Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.

The authors calculated the progression rate (ΔFS) using the total revised ALS Functional Rating Scale (ALSFRS-R) and symptom duration at diagnosis in 82 Japanese patients with ALS. Survival (death or tracheostomy) differed significantly with the ΔFS and postdiagnostic period according to log-rank testing, but Cox proportional hazards modeling revealed no strong association between total ALSFRS-R and mortality, suggesting that the ΔFS provides an additional predictive index beyond ALSFRS-R alone.

Bone Marrow Stromal Cells That Enhanced Fibroblast Growth Factor-2 Secretion by Herpes Simplex Virus Vector Improve Neurological Outcome After Transient Focal Cerebral Ischemia in Rats

Background and Purpose— Fibroblast growth factor-2 (FGF-2) administration and bone marrow stromal cell (MSC) transplantation could improve neurological deficits after occlusive cerebrovascular disease. In the present study, we examined the effects of neurological improvement after transient middle cerebral artery occlusion (MCAO) in rats by a novel therapeutic strategy with FGF-2 gene–transferred MSCs by the herpes simplex virus type 1 (HSV-1) vector. Methods— Adult Wistar rats were anesthetized. Nonmodified MSCs, FGF-2–modified MSCs with HSV-1 1764/-4/pR19/ssIL2-FGF-2, or PBS was administered intracerebrally 24 hours after transient right MCAO. All animals underwent behavioral tests for 21 days, and the infarction volume with 2-3-5-triphenylterazolium was detected 3 days and 14 days after the MCAO. Three days and 7 days after the MCAO, the FGF-2 production in the ipsilateral hemisphere of the MCAO was measured with ELISA. Seven and 14 days after the MCAO, immunohistochemical staining for FGF-2 was applied. Results— The stroke animals receiving FGF-2–modified MSCs demonstrated significant functional recovery compared with the other groups. Fourteen days after the MCAO, there was a significant reduction in infarction volume only in FGF-2–modified MSC-treated group. FGF-2 production in the FGF-2–modified MSC-treated brain was significantly higher compared with the other groups at 3 and 7 days after MCAO. Administrated FGF-2–modified MSCs strongly expressed the FGF-2 protein, which was proven by ELISA. Conclusions— Our data suggest that the FGF-2 gene–modified MSCs with the HSV-1 vector can contribute to remarkable functional recovery after stroke compared with MSCs transplantation alone.

Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis

Objective To define patterns of spread through the order of lower motor neuron involvement (first, second or third order), relationships between interval or sites of affected areas from onset to involvement of a second region, and prognosis, including 5 year survival, normal preservation of motor function at onset of respiratory symptoms and cumulative occurrence of each region and direction of spread. Method 150 patients with sporadic amyotrophic lateral sclerosis (ALS) underwent follow-up at 3 month intervals until the appearance of respiratory symptoms. Symptom appearances were determined using the revised version of the ALS Functional Rating Scale. Result Median survival with combined type onset (two regions simultaneously) was shorter (18 months) than with bulbar onset (26 months, p=0.01). The interval from onset to involvement of the second region correlated significantly with survival, independent of particular combinations. 5 year survival rate was 21% for lower limb onset, 18% for upper limb onset and 16% for bulbar onset. No patient with a rapid spread pattern (two regions within 3 months from onset) survived >5 years. Early manifestations of bulbar symptoms within 1 year were associated with worse survival (p<0.001) although no significant difference in survival was seen between groups with and without bulbar symptoms (p=0.51). In terms of cumulative occurrence, symptoms spread longitudinally to adjacent regions. Bulbar function remained preserved in 27%, lower limb function in 10% and upper limb function in 2.7%. Conclusion The interval between onset and involvement of the second region is an important predictor of survival. The data support the contiguous anatomical propagation of lower motor neuron involvement in sporadic ALS.

ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.

Expression of Th1/Th2-Related Chemokine Receptors on Peripheral T Cells and Correlation with Clinical Disease Activity in Patients with Multiple Sclerosis

Th1 cells play an important role in the pathogenesis of multiple sclerosis (MS), a disease likely linked to an autoimmune process. We measured the levels of chemokines in serum or cerebrospinal fluid (CSF) samples by ELISA, and also studied the expression of Th1-related CXCR3/CCR5 chemokine receptors and Th2-related CCR4/CCR3 chemokine receptors on blood cells from MS patients using three-color flow cytometry. The Bonferroni correction was used for the statistical analysis. The levels of CXCL10, CCL3, and CCL5 in the CSF samples for the MS groups were significantly higher than those for the control group. However, the levels of CCL2 in both the CSF and serum samples for the remission group were significantly higher than those for the active group. The percentage of CXCR3-expressing CD4+ T cells in patients with MS was significantly elevated compared with the healthy controls. Moreover, MS patients in an active phase showed a more increased CD4+CXCR3+/CD4+CCR4+ ratio than patients in a remission phase. The increased percentage of CD4+CXCR3+ cells in the blood was associated with relapses in MS. This study suggested that the CD4+CXCR3+/CD4+CCR4+ ratio could be a sensitive maker of immune dysfunction in MS.

Herpes simplex Virus Myelitis: Clinical Manifestations and Diagnosis by the Polymerase Chain Reaction Method

Herpes simplex virus (HSV) myelitis has previously been reported to be a form of acute ascending necrotizing myelitis caused by HSV type 2 (HSV-2). We studied neurological symptoms, clinical course, magnetic resonance imaging (MRI) findings, and diagnosis by polymerase chain reaction (PCR) methods in 9 patients with HSV myelitis. In 6 cases, disease onset was marked by sensorimotor disturbances of lower extremities and urinary disturbances, with the transverse myelopathy gradually ascending to the cervicothoracic spinal cord level. The other 3 cases showed transverse myelopathy without an ascending pattern. Six cases showed acute progression, while 3 cases showed a subacute course. There were 2 cases with recurrent episodes. Three patients recovered, however, in the remaining 6 patients severe sequelae such as paraplegia persisted despite antiviral therapy. MRI showed a hyperintense lesion on T2-weighted images. Gadolinium enhancement was observed in 2 cases, and 1 case showed a hyperintense lesion both on T1- and on T2-weighted images, suggesting hemorrhagic necrosis. HSV-2 was detected by PCR techniques in all 6 cases with an ascending pattern. HSV-1 DNA was detected in 2 and HSV-2 DNA in 1 of the 3 cases with a nonascending pattern. Our findings demonstrate diverse clinical manifestations of HSV myelitis.

A pilot study of dehydroepiandrosterone sulfate in myotonic dystrophy

We studied the effect of IV administration of a dehydroepiandrosterone sulfate (DHEAS) preparation (200 mg/day for 8 weeks) in 11 patients with myotonic dystrophy (MyD). After DHEAS, activities of daily living improved, muscle strength increased, and myotonia decreased. Conduction block and premature beats also improved in the four patients with cardiac involvement. This pilot study may provide a rationale for a controlled study of DHEAS in MyD.

Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy

Polyglutamine tracts encoded by trinucleotide CAG repeats have been found in some transcription factors. Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). To study the role of AR as a transcription factor in SBMA, we constructed AR genes encoding expanded polyglutamine tracts (repeat numbers = 52, 92, 132, and 212), and analyzed AR-induced transcriptional activation in NG108-15 cells. We found that AR-induced transcriptional activation gradually decreased with increasing glutamine repeat numbers, and polyglutamine expansion caused a specific reduction in transcription activity in motor neurons. However, the degree of reduction was slight in comparison with the normal AR gene and that of SBMA. Thus, subtle disorders of transcriptional control may occur in SBMA.

Visual field defects of optic neuritis in neuromyelitis optica compared with multiple sclerosis

BackgroundNeuromyelitis optica (NMO) is an inflammatory demyelinating disease that predominantly affects the optic nerves and the spinal cord, and is possibly mediated by an immune mechanism distinct from that of multiple sclerosis (MS). Central scotoma is recognized as a characteristic visual field defect pattern of optic neuritis (ON), however, the differing pathogenic mechanisms of NMO and MS may result in different patterns of visual field defects for ON.MethodsMedical records of 15 patients with NMO and 20 patients with MS having ON were retrospectively analyzed. A thorough systemic and neurological examination was performed for evaluating ON. The total number of relapses of ON and visual fields was investigated. Visual fields were obtained by Goldmann perimeter with each ON relapse.ResultsAll MS patients experienced central scotoma, with 90% of them showing central scotoma with every ON relapse. However, 53% of NMO patients showed central scotoma with every ON relapse (p = 0.022), and the remaining 47% of patients experienced non-central scotoma (altitudinal, quadrant, three quadrant, hemianopia, and bitemporal hemianopia). Thirteen percent of NMO patients did not experience central scotoma during their disease course. Altitudinal hemianopia was the most frequent non-central scotoma pattern in NMO.ConclusionsNMO patients showed higher incidence of non-central scotoma than MS, and altitudinal hemianopia may be characteristic of ON occurring in NMO. As altitudinal hemianopia is highly characteristic of ischemic optic neuropathy, we suggest that an ischemic mechanism mediated by anti-aquaporin-4 antibody may play a role in ON in NMO patients.

Increased serum matrix metalloproteinase-9 in neuromyelitis optica: implication of disruption of blood-brain barrier.

Matrix metalloproteinase-9 (MMP-9) plays an important role in some neuroinflammatory diseases through the blood-brain barrier (BBB) disruption. To investigate the pathogenicity of MMP-9 in neuromyelitis optica (NMO), serum and CSF MMP-9 concentrations were measured in 13 NMO and 15 multiple sclerosis (MS) patients and 14 healthy controls, and correlated with clinical and laboratorial parameters. Serum MMP-9 concentrations were significantly higher in NMO than MS and controls, and correlated with EDSS score, CSF/serum albumin ratio, and CSF IL-8 concentrations. Our results indicate that MMP-9, promoted by elevated IL-8 activation, plays a crucial role in the pathogenesis of NMO through the BBB disruption.