Hiroya Utsumi

Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15q13-15

To date, three loci for autosomal recessive hereditary spastic paraplegia (ARHSP) linked to chromosomes 8p12‐q13, 16qter, and 15q13–15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the “complicated” form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12‐q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13–15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3‐centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive spastic paraplegia, maps to chromosome 15q13–15. Ann Neurol 2000;48:108–112

Clinical implication of peripheral CD4+CD25+ regulatory T cells and Th17 cells in myasthenia gravis patients.

Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors (AChR) of the skeletal muscles. CD4 T cells help B cells to produce antibodies through their production of cytokines or chemokines. In this study, we evaluated the frequency of regulatory (Treg) and IL-17 producing CD4 T-cell subsets (Th17) in peripheral blood mononuclear cells (PBMCs) of patients with MG. The transcription factor, forkhead transcription factor (Foxp3), is essential for T-cell regulatory function, and the orphan nuclear receptor, RORgammaT, is important in Th17 cell differentiation. In MG patients, Foxp3 mRNA expression in PBMCs was lower than those in healthy subjects (p=0.007), while there was no significant difference of RORgammaT mRNA expression between MG patients and healthy subjects. Glucocorticoid-induced tumour-necrosis-factor receptor-related protein (GITR) is expressed predominantly on CD4(+)CD25(+) Treg cells. We found that the number of GITR(+)CD4(+)CD25(+) T cells in peripheral lymphocytes in MG patients was lower than that in healthy subjects (P<0.01). In addition, there was a significant positive correlation between the change of the frequency of GITR(+)CD4(+)CD25(+) T cells and the changing rate in quantitative myasthenia gravis scores (%) (p=0.03). Furthermore, there was a significant negative correlation between the change of the percentage of GITR(+)CD4(+)CD25(+) T cells (% lymphocytes) and the changing rate of daily PSL doses (%) (P=0.002). The relative RORgammaT levels in PBMCs negatively correlated with the Th1/Th2 ratio in CD4(+) cells in MG patients (p=0.014). In conclusion, our findings suggest that Th17 cells affect the production of autoantibodies through their influence on the Th1- and Th2-cytokine balance in PBMCs of MG patients. On the other hand, Treg cells are suggested to be involved in the clinical condition or severity of MG disease.

The MG-QOL15 Japanese version: validation and associations with clinical factors.

Our study aim was to produce a Japanese translation of the 15‐item Myasthenia Gravis Quality‐of‐Life Scale (MG‐QOL15), assess its reliability and validity, and examine clinical factors affecting self‐perceived QOL in MG.

Relationship between NMO-antibody and anti-MOG antibody in optic neuritis.

Background: Damage to astrocytes by anti-aquaporin-4 antibody (AQP4-Ab), also known as NMO antibody, has been implicated as the cause of neuromyelitis optica. Myelin oligodendrocyte glycoprotein (MOG) is well known as the causative protein of multiple sclerosis (MS). MOG antigen is currently considered as a cause of optic neuritis (ON) associated with MS because immunization with MOG antigen derived from oligodendrocytes induces murine ON with myelitis. We investigated the relationship between NMO antibody (NMO-Ab) and anti-MOG antibody (MOG-Ab) and potential in patients with ON for recovery of vision. Methods: Thirty-three eyes of 23 patients with ON were studied. At presentation, serum NMO-Ab was measured by immunofluorescence using HEK 293 cells transfected with AQP4–GFP, and anti-MOG1–125 antibody was measured by enzyme-linked immunosorbent assay. MOG-Ab seropositivity was defined by comparing with MOG-Ab level obtained from 8 healthy normal subjects. Results: Eleven (47%) of 23 ON patients were NMO-Ab seropositive, while 8 (34%) of the 23 patients were MOG-Ab seropositive. Six (26%) of 23 patients were seropositive for both NMO-Ab and MOG-Ab. Ten (43%) of 23 patients were seronegative for both antibodies. Three (50%) of 6 eyes of patients seropositive for both antibodies did not respond to corticosteroid pulse therapy and plasmapheresis, and visual acuity remained unchanged. In the NMO-Ab(−)/MOG-Ab(−) group, visual acuity improved significantly (P < 0.0001). In the other 3 groups (NMO-Ab(+)/MOG-Ab(+), NMO-Ab(+)/MOG-Ab(−), and NMO-Ab(−)/MOG-Ab(+)), visual acuity did not change significantly (P = 0.53, 0.42, and 0.45, respectively). Conclusion: NMO-Ab and MOG-Ab could be potential biomarkers to determine visual prognosis in patients with ON.

Excessive daytime sleepiness and sleep episodes in Japanese patients with Parkinson's disease

In Parkinsons disease (PD), sudden unexpected sleep episodes and excessive daytime sleepiness (EDS) while driving and engaging in social activities are important problems. We conducted a multi-center study to clarify the prevalence and contributing factor of EDS and sleep episodes in Japanese patients with PD. We evaluated 188 patients with PD (85 men, 103 women) and 144 age-matched controls for sleepiness. EDS was defined as an Epworth sleepiness scale (ESS) score of >or=10. ESS score was significantly higher (6.6+/-4.2 vs. 5.6+/-3.8) and prevalence of sleep episodes was higher in PD than in controls (6.4% vs. 0.7%). PD patients with EDS were more likely to have sleep episodes (22.5% vs. 2.0%), higher score for disease severity and depressive symptoms, and on higher dose of dopaminergic agents than those without EDS. However, there were no differences in nocturnal disturbances between the two groups. ESS score was not different between patients taking ergot and non-ergot dopamine agonists. Logistic regression analysis demonstrated that mental state, total dose of dopaminergic agents, and ESS score were significant predictors of sleep episodes. ESS score of >or=10 had 75% sensitivity and 82.4% specificity for sleep episodes. These results suggest that sleepiness in PD is dependent on disease itself and dopaminergic treatment rather than nocturnal disturbances.

Characteristics of sleep disturbances in Japanese patients with Parkinson's disease. A study using Parkinson's disease sleep scale

The present multicenter cross‐sectional study was performed using semistructured questionnaires to determine the contributing factors of sleep disturbances in Japanese patients with Parkinsons disease (PD). We used the Parkinsons disease sleep scale (PDSS, Japanese version). All data were obtained by means of interviewed questionnaire and physical examination by neurologists. The study was carried out between April 2005 and December 2005 at eight university hospitals and affiliated facilities in the Kanto area of Japan. A total of 188 (85 men and 103 women) PD patients and 144 controls (64 men and 80 women) were included. Stepwise regression analysis identified complications of treatment, depression, age, and disease duration as significant risk factors of sleep disturbances in PD. Significant differences in total PDSS score were observed between Hoehn & Yahr (H&Y) Stages 1 and 4, between H&Y Stages 2 and 4, and between H&Y stages 3 and 4 (Bonferroni test). The results of this survey suggested that complications due to treatment (dyskinesia, wearing off, on–off), depressive state, and disease stage are significant determinants of sleep disorders in Japanese patients with PD. We speculate that the reduction of neurotransmitters involved in the sleep–wakefulness mechanism and degeneration of neurons progress together in parallel with deterioration of motor function.

Correlation between depressive symptoms and nocturnal disturbances in Japanese patients with Parkinson's disease.

Depression and nocturnal disturbances are frequent in patients with Parkinsons disease (PD). The aim of this study was to determine the correlation between depressive symptoms and nocturnal disturbances in patients with PD in Japan. The subjects of this multi-center cross-sectional study were 188 patients with PD and 144 age-matched controls who were assessed for nocturnal disturbances by the Parkinsons disease sleep scale (PDSS) and for depressive symptoms by Zung Self-Rating Depression Scale (SDS). Depressive symptoms (SDS score of > or =40) were identified in 122 patients (64.9%). The SDS was significantly higher in PD patients than control subjects. The stepwise regression model identified PDSS (p<0.001) and Unified Parkinsons Disease Rating Scale I (mental state) (p=0.002) as significant determinants of SDS. Stepwise regression analysis identified item 15 (daytime sleepiness) (p=0.002), item 13 (early morning tremor) (p=0.008), item 12 (nocturnal dystonia) (p=0.015), and item 3 (sleep maintenance insomnia) (p=0.026) as significant predictors of SDS. Our results indicated that depressive symptoms in PD correlate significantly with nocturnal disturbances, and that daytime sleepiness, dystonia, tremor and sleep fragmentation are the most common nocturnal disturbances in depressed patients with PD.

Fatigue in Japanese patients with Parkinson's disease: a study using Parkinson fatigue scale.

The objective of this multicenter cross‐sectional study was to determine the prevalence of fatigue and factors contributing to it in a large sample of Japanese patients with Parkinsons disease (PD). We used the 16‐item Parkinson Fatigue Scale (PFS‐16), which was designed to assess fatigue exclusively associated with PD. We carried out this study using PFS‐16, the Unified Parkinsons Disease Rating Scale, Zungs Self‐Rating Depression Scale, Parkinsons Disease Sleep Scale (PDSS), and the PD quality of life (QOL) scale (PDQ‐39) by interview using questionnaires and physical examination by neurologists in 361 nondemented PD patients. Fatigue (an average PFS score of 3.3 or greater) was revealed in 151 patients (41.8%). Multiple logistic regression analysis indicated that the significant independent variables related to the presence of fatigue were the scores of PDSS and PDQ‐39. Depression score was not a significant contributing factor. Our study revealed that the prevalence of fatigue in Japanese PD patients is as high as that in Western countries, and that fatigue is a relatively independent symptom, although sleep disturbance may be associated with fatigue. Since fatigue is significantly related to QOL reduction, therapeutic interventions including treatment of sleep disturbance are important.

Factors associated with depressive state in patients with myasthenia gravis: a multicentre cross-sectional study

Objectives The objective of this study was to examine clinical factors associated with depressive state in patients with myasthenia gravis (MG). Design Cross-sectional study. Setting and participants We evaluated 287 consecutive cases of MG seen at six neurological centres located in Eastern Japan. Outcome measures All MG patients completed the Japanese version of the Beck Depression Inventory–Second Edition (BDI-II). Disease severity was determined according to the MG Foundation of America (MGFA) quantitative MG score, MG activities of daily living scale and MG composite scale (MG composite). Clinical state following treatment was categorised according to MGFA postintervention status. Associations between detailed clinical parameters of MG and BDI-II score were then examined statistically. Results Mean BDI-II score for patients with MG (11.0±8.1) did not differ substantially from and overlapped with that reported as the Japanese standard (8.7±6.4). The mean +2 SDs for the Japanese standard is 21.5, approximately equal to the cut-off level indicative of moderate or worse depression (>20 points) in the original English version. We thus defined BDI-II >21.5 as depressive state, with a frequency of 13.6% in patients with MG. Multivariate logistic regression analysis revealed current dose of oral prednisolone (OR 1.09, 95% CI 1.02 to 1.17; p=0.01), unchanged MGFA postintervention status (OR 3.55, 95% CI 1.18 to 10.71; p=0.02), time since onset (OR 0.93, 95% CI 0.87 to 0.99; p=0.03) and MG composite (OR 1.16, 95% CI 1.00 to 1.34; p=0.046) as factors independently associated with depressive state in MG. Conclusions Dose of oral corticosteroids appears to represent the major factor associated with depressive state in MG. Unchanged status despite treatment and early disease stage are also significant background factors for depressive state, along with disease severity.

Presynaptic l-type Ca2+ channels on excessive dopamine release from rat caudate putamen

We investigated by means of behavioral and neurochemical studies the role of the nerve terminal L-type voltage sensitive Ca(2)+ channel on dopamine (DA) release. Microinjection of Bay K 8644 (BAYK), an L-type Ca(2)+ channel stimulant, into the rat caudate putamen increased locomotor activity and rearing behavior in a dose-dependent manner, whereas injections into the amygdala had no effect. DA receptor antagonists significantly blocked BAYK-induced hyperactivity. Significant increases of extracellular DA levels were detected by microdialysis 20 min after BAYK administration into caudate putamen and then declined. This increase was influenced by tetrodotoxin, an axonal Na(+) channel blocker. Pretreatment with nimodipine and nicardipine, but not nifedipine, which are 1, 4-dihydropyridine L-type Ca(2)+ channel antagonists, administered into the caudate putamen significantly blocked BAYK-induced hyperactivity and DA efflux. These results indicate that the extraordinary DA release in the caudate putamen was mediated by extreme stimulation of the nicardipine and nimodipine-sensitive L-type Ca(2)+ channel present in the nerve terminal of striatal DA neurons.