Mieko Ogino

Association of anti-GM2 antibodies in Guillain-Barré syndrome with acute cytomegalovirus infection

We examined serum anti-cytomegalovirus (CMV) and anti-ganglioside antibodies by ELISA in 51 patients with Guillain-Barré syndrome (GBS), and titers were compared with those from 47 normal and 74 disease controls. Three GBS patients with IgM anti-CMV antibodies had high titers of IgM and IgG anti-GM2 antibodies. The other GBS patients without IgM anti-CMV antibodies, and the normal and disease controls except one of 6 non-GBS patients with acute CMV infections had no anti-GM2 antibodies. The titers of anti-GM2 antibodies decreased on absorption with CMV-infected cells. These findings suggest that anti-GM2 antibodies are associated with acute CMV infections in GBS patients.

Reduction rate of body mass index predicts prognosis for survival in amyotrophic lateral sclerosis: A multicenter study in Japan

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3–3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

Abnormalities of spinal magnetic resonance images implicate clinical variability in human T-cell lymphotropic virus type I–associated myelopathy

This study investigated the role of human T-cell lymphotropic virus type I HTLV-I infection in 11 patients who developed slowly progressive myelopathy with abnormal spinal cord lesions. The authors performed clinical and neuroradiological examinations and calculated the odds that an HTLV-I-infected individual of a specific genotype, age, and provirus load has HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Anti-HTLV-I antibodies were present in both the serum and cerebrospinal fluid in all of the patients. Abnormal magnetic resonance imaging (MRI) lesions were classified as cervical to thoracic type (CT type), cervical type (C type), and thoracic type (T type). In each type, there was swelling of the spinal cords with high-intensity lesions, which were located mainly in bilateral posterior columns, posterior horns, or lateral columns. Virological and immunological analyses revealed that all patients showed a high risk of developing HAM/TSP. These 11 patients may have developed HAM/TSP, as manifested by spinal cord abnormalities shown on MRI. These MRIs implicate clinical variability of HAM/TSP, which may indicate active-early stages of HAM/TSP lesions.

Tracheostomy with invasive ventilation for ALS patients: Neurologists’ roles in the US and Japan

Abstract Our objective was to determine whether substantial differences in rates of TIV utilization in the U.S. and Japan are associated with the role of the treating neurologist. Questionnaires in English and Japanese were sent to neurologists who treated ALS patients in both countries. Questions included queries about rates of TIV use in their practices, level of encouragement of TIV use, the role of the neurologist in TIV decision making, management of patient/family requests to discontinue TIV once initiated, and personal choices if neurologists themselves had ALS. Results showed that 84% of American neurologists reported fewer than 10% of their patients had TIV, compared to 32% of Japanese. Americans less often encouraged TIV use (79% of American and 36% of Japanese seldom or never suggested or encouraged TIV). Finally, neurologists were asked whether they would choose TIV for themselves in the hypothetical scenario where they had ALS: over 70% of both groups declined TIV for themselves. In conclusion, consistent with past findings, Japanese neurologists were more likely to recommend TIV and more of their patients received TIV. Both groups believed their recommendations influence patient decisions. While Americans seldom recommended TIV to patients and most would not choose TIV for themselves, Japanese neurologists’ recommendations and personal choices diverged.

I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3β signaling pathway

Leucine-rich repeat kinase 2 (LRRK2) is the causative molecule of the autosomal dominant hereditary form of Parkinsons disease (PD), PARK8, which was originally defined in a study of a Japanese family (the Sagamihara family) harboring the I2020T mutation in the kinase domain. Although a number of reported studies have focused on cell death mediated by mutant LRRK2, details of the pathogenetic effect of LRRK2 still remain to be elucidated. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated induced pluripotent stem cells (iPSC) derived from fibroblasts of PD patients with I2020T LRRK2 in the Sagamihara family. We found that I2020T mutant LRRK2 iPSC-derived neurons released less dopamine than control-iPSC-derived neurons. Furthermore, we demonstrated that patient iPSC-derived neurons had a lower phospho-AKT level than control-iPSC-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. Interestingly, patient iPSC-derived neurons exhibited activation of glycogen synthase kinase-3β (GSK-3β) and high Tau phosphorylation. In addition, the postmortem brain of the patient from whom the iPSC had been established exhibited deposition of neurofibrillary tangles as well as increased Tau phosphorylation in neurons. These results suggest that I2020T LRRK2-iPSC could be a promising new tool for reproducing the pathology of PD in the brain caused by the I2020T mutation, and applicable as a model in studies of targeted therapeutics.

Lewy body pathology in a patient with a homozygous Parkin deletion

We report neuropathologic findings in a patient with homozygous deletions of exons 2 to 4 of parkin.

Tryptophan-immobilized Column-based Immunoadsorption as the Choice Method for Plasmapheresis in Guillain–Barré Syndrome

Abstract:  Plasmapheresis is widely performed as treatment for patients with Guillain–Barré syndrome (GBS) in the acute phase. As tryptophan‐immobilized column‐based immunoadsorption (Tr‐IA) is a safer method than either double‐filtration plasmapheresis (DFPP) or plasma exchange (PE), we investigated whether or not Tr‐IA is as effective as other methods, and should be selected as the procedure of choice in patients with GBS. We retrospectively compared clinical outcomes, using Hughes grading, in GBS patients treated with Tr‐IA, DFPP or PE. The outcome in the Tr‐IA group was also compared historically with patients treated by PE in seven previous studies. We studied 34 patients with GBS: 20 were treated with Tr‐IA, 11 with DFPP, and 3 with PE. The age, sex, duration from onset to initiation of treatment, and Hughes grade at entry did not differ among the Tr‐IA, DFPP and PE groups. There was no significant difference in outcomes among these three groups, nor was there a significant difference between the outcomes in the Tr‐IA and DFPP groups with respect to subgroups of Hughes grade at entry. Also, our Tr‐IA group did not show a different outcome from the previously reported patients treated with PE. The frequency of complications in our Tr‐IA group is significantly lower than that in both our DFPP group, and in the previously reported cases of patients treated with PE. Tr‐IA, DFPP and PE have almost the same efficacy in patients with GBS, but Tr‐IA is recommended as the plasmapheresis method of choice because of its safety.

Japanese and American ALS patient preferences regarding TIV (tracheostomy with invasive ventilation): A cross-national survey

Abstract Substantial disparities in TIV utilization rates among ALS patients have been observed, with rates in Japan far exceeding rates in the United States. Our objective was to elicit national preferences and their determinants. We predicted more Japanese than American patients would desire TIV, as would sicker patients, those already using non-invasive interventions, and those with more positive mood and outlook. Patients were enrolled in five U.S. states and six Japanese regions. Eligible patients completed surveys during clinic visits (U.S.) or at home (Japan). Survey responses were in multiple-choice format and took about 15 min to complete. One hundred and fifty-six Americans and 66 Japanese patients participated. Contrary to expectations, Japanese patients were more likely to oppose TIV, as were those on 24-h NIV and patients who knew someone using TIV. Most Japanese and American patients with advanced respiratory impairment were undecided or opposed to TIV, while nearly 20% in both countries were in favor. Finally, patients who favored TIV or who were undecided had more energy, greater wish to live, and more sense of control over ALS management. In conclusion, factors other than patient preferences, such as neurologist preferences, caregiver attitudes and perhaps lack of advance planning, may influence probability of TIV utilization.

Syntactic comprehension in patients with amyotrophic lateral sclerosis.

Recent neuropsychological studies of patients with amyotrophic lateral sclerosis (ALS) have demonstrated that some patients have aphasic symptoms, including impaired syntactic comprehension. However, it is not known if syntactic comprehension disorder is related to executive and visuospatial dysfunction. In this study, we evaluated syntactic comprehension using the Syntax Test for Aphasia (STA) auditory comprehension task, frontal executive function using the Frontal Assessment Battery (FAB), visuospatial function using Ravens Coloured Progressive Matrices (RCPM), and dementia using the Hasegawa Dementia Scale-Revised (HDS-R) in 25 patients with ALS. Of the 25 patients, 18 (72%) had syntactic comprehension disorder (STA score < IV), nine (36%) had frontal executive dysfunction (FAB score < 14), six (24%) had visuospatial dysfunction (RCPM score < 24), and none had dementia (HDS-R score < 20). Nine of the 18 patients with syntactic comprehension disorder (50%) passed the FAB and RCPM. Although sample size was small, these patients had a low STA score but normal FAB and RCPM score. All patients with bulbar onset ALS had syntactic comprehension disorder. These results indicate that it might be necessary to assess syntactic comprehension in patients with bulbar onset ALS. The implications of these findings are discussed in relation to the pathological continuum of ALS.

Sniff Nasal Inspiratory Pressure in Healthy Japanese Subjects: Mean Values and Lower Limits of Normal

Background: When assessing respiratory muscle strength using sniff nasal inspiratory pressure (SNIP), it is important to consider ethnic differences. Therefore, it is necessary to determine the mean values and lower limits of normal for SNIP in the Japanese population. Objective: To determine the mean values and lower limits of normal for SNIP, which is used as an assessment of inspiratory muscle strength, in healthy Japanese subjects. Methods: A total of 223 healthy Japanese volunteers (112 men, 111 women), aged 18–69 years, were studied; none had a history of pulmonary disease, heart disease, neuromuscular disease or sinusitis. To measure SNIP, a nasal plug was inserted into one nostril and the mouth was kept closed. Each subject was asked to take short, sharp sniffs with maximal effort from functional residual volume. Results: Based on the intraclass correlation coefficient, SNIP measurements showed good reproducibility in both men and women. The mean SNIP values were 76.8 ± 28.9 cm H2O in men and 60.0 ± 20.0 cm H2O in women; the values were significantly higher in men than in women (p < 0.01). On stepwise multiple linear regression analysis, the SNIP values were negatively related to age in men and positively related to body mass index (BMI) in women. The lower limits of normal for SNIP were 32.9 cm H2O in men and 28.8 cm H2O in women. Conclusions: In healthy Japanese subjects, the mean SNIP value was higher in men than in women. In Japanese subjects, SNIP values appear to be related to age in men and BMI in women.