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To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association (P= 6.5 × 10−7) that was replicated in additional Japanese samples (P= 2.9 × 10−6. OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P= 5.0 × 10-15. Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples (P=0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution inPLA2G4Cthat encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

Background: In Japan, pollen counts increased between 1977 and 1987, including three peaks (1978- 1980, 1982, 1984-1986) coinciding with Kawasaki disease (KD) outbreaks. Epidemiological findings have been gradually accumulated that KD and related specific intractable diseases and further cancers may be correlated to pollen exposure (PE). Methods and results: To elucidate the effects of PE on occurrence of thyroid, skin, esophagus, kidney and ovary cancers, and leukemia, multiple myeloma and all cancers, we evaluated the annual onsets of malignant tumors in relation to pollen counts using data from a national database. Increased rates of these cancers were observed during pollen counts increasing period between 1977 and 1987. Significant correlations were observed between the annual number of newly registered patients (nRPs) and the annual pollen levels (PL) measured with a lag of 2 years for skin and kidney cancers, 4 years for thyroid cancer, 6 years for skin, esophagus cancers, leukemia and multiple myeloma, 8 years for thyroid cancer, and 2,3 and 6 years for all cancers. Peaks of number of thyroid cancer in 2013, 1990 and 1980 are discussed about as compared with other cancers regarding effect of radioactive pollutants occurred from three nuclear plant accidents. Conclusion: Data suggest newly that the cumulative effects of PE within 2,3,4,6,8 years prior to diagnosis might possibly trigger incidence of eight cancers and malignant tumors.

he inference that this paper points out is that the stimulating environmental factor behind why the SARS-CoV-2 epidemic occurred in Wuhan is probably pollen from the plant kingdom. We started in 2003 to point out the epidemiological fact that Kawasaki disease is probably a Pollen-Induced Disease (PID) triggered by pollen exposure.

Objective: To establish a practical method for discriminating dementia groups and healthy elderlies, by using scalp-recorded electroencephalograms (EEGs). Methods: 16-ch EEGs were recorded during resting state for 39 dementia groups and 11 healthy elderlies. The connectivity between any two electrodes was estimated by synchronization likelihood (SL). The brain networks were constructed by normalized SL values. The present leave-one-out cross validation (LOOCV) required the Euclidean distance between any two subjects having 120-dimensional vectors concerned with the SL values for six frequency bands. In order to investigate factors which would affect the LOOCV results, principal component analysis (PCA) was applied to all the subjects. Results: The accuracy for the upper alpha yielded more than 80% and 70% in the dementia groups and the healthy elderlies, respectively. The LOOCV result could be explained in terms of brain networks such as executive control network (ECN) and default mode network (DMN) characterized by factor loadings of principal components. Conclusions: Dementia groups and healthy elderlies could be characterized by principal components of SL values between all the electrode pairs, even less connections, which revealed disruption and preservation of DMN and ECN. Significance: This study will provide a simple and practical method for discriminating dementia groups from healthy elderlies by scalp-recorded EEGs.

Novel Coronavirus Disease (COVID-19) swept the world and Led to a global pandemic SARS-CoV-2, which is thought to have derived from bats as their reservoir hosts, has over time and similarly as with SARS-CoV, combined with human angiotensin converting enzyme 2 (ACE2) Thus, this caused infections in cells and established them into a human infectious disease (COVID-19) Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1SS, IL-8, TNF-a, and other chemokines such as G-CSF, IP10, MCPl, to develop an increase the inflammatory responses In the case of COVID-19, it revealed that excessive inflammatory responses occur, and that the exaggerated proinflammatory cytokines and chemokines are detected in COVID-19 patients' sera resulting in cytokine release syndrome (CRS) or cytokine storm (CS) This causes coagulation abnormalities, excessive oxidation development, vital organ damages, immune system failure, and finally, progresses to disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) Additionally, excessive inflammatory responses lead to mitochondrial dysfunction due to progressive and persistent stress which leads to cells and mitochondrial fracturing products containing mitochondrial DNA and damaged cell debris which in turn are involved in the chronic excessive inflammation as damage-associated molecular patterns (DAMPs) Thus, respiratory infection progressively leads to DIC from acute respiratory distress syndrome (ARDS) including vascular endothelial cell damages and coagulation-fibrinolysis system disorders Then, this worsens to central nervous system disorders, renal failure, liver failure, and finally to MOF With regards to treatments for COVID-19, the followings are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients Firstly, the administering of Favipiravir for the suppression of SARS-CoV-2, and Nafamostat for the inhibition of ACE2 function should be considered Then, the administration of anti-rheumatic drugs (monoclonal antibodies which combine with the leading cytokines (IL-1SS, IL-6) and/or cytokine receptors such as Tocilizumab) Finally, melatonin may be effective under recognition of the pathology of CRS/CS for the improvement of mitochondrial function The paper will further explore these subjects with reports mostly from China and Europe Новая коронавирусная болезнь (COVID-19) охватила весь мир и привела к глобальной пандемии Предполагается, что возбудитель заболевания - вирус SARS-CoV-2 использует летучих мышей в качестве промежуточных хозяев Попадая в организм человека, так же как и SARS-CoV, SARS-CoV-2 начинает взаимодействовать с ангиотензин-превращающим ферментом 2 (ACE2), рецептором на поверхности клетки В результате такого взаимодействия вирус проникает в клетки и запускает инфекционный процесс в организме человека, а заболевание получило название COVID-19 В ответ на вирусную инфекцию активируется система врожденного иммунитета, что приводит к усилению производства и высвобождению провоспалительных цитокинов, таких как IL-6, IL-1SS, IL-8, TNF-a, а также хемокинов, таких как G-CSF, IP10, MCP1, и развитию воспалительной реакции COVID-19 сопровождается чрезмерным воспалением и повышенным содержанием провоспалительных цитокинов и хемокинов в сыворотке крови, что свидетельствует о развитии синдрома высвобождения цитокинов, или «цитокинового шторма» В ходе развивающегося синдрома высвобождения цитокинов происходят нарушения коагуляции, чрезмерный оксидативный стресс, повреждение жизненно важных органов и нарушение функций иммунной системы Эти проявления прогрессируют и в конце концов приводят к развитию синдрома диссеминированного внутрисосудистого свертывания и полиорганной недостаточности Чрезмерные воспалительные реакции и прогрессирующий оксидативный стресс вызывают дисфункцию и повреждение митохондрий В результате в зоне воспаления накапливаются фрагменты разрушенных клеток и остатки разрушенных митохондрий, содержащие митохондриальную ДНК Эти продукты разрушения клеток, в свою очередь, действуя как молекулярные паттерны, связанные с повреждением, пролонгируют острое воспаление до развития хронического чрезмерного воспаления Таким образом, вирус, первоначально попадая в легкие, инициирует острый респираторный дистресс-синдром с последующим развитием синдрома диссеминированного внутрисосудистого свертывания Этот синдром сопровождается повреждением эндотелиальных клеток сосудов и нарушением системы свертывания крови Прогрессирование этих нарушений приводит к расстройствам центральной нервной системы, почечной и печеночной недостаточности и, наконец, к полиорганной недостаточности Лечение пациентов с COVID-19 должно быть основано на подавлении чрезмерного воспалительного ответа и «цитокинового шторма» Для этого есть несколько возможностей Целесообразно рассмотреть, во-первых, назначение фавипиравира для снижения активности SARS-CoV-2 и нафамостата для подавления функции ACE2, а во-вторых, назначение противоревматических препаратов (таких как моноклональные антитела, которые нейтрализуют или цитокины IL-1SS и IL-6, или рецепторы этих цитокинов, например тоцилизумаб) Наконец, для улучшения нарушенных функции митохондрий при синдроме высвобождения цитокинов/«цитокиновом шторме» может оказаться эффективным мелатонин В обзоре все эти вопросы рассмотрены в основном на материалах отчетов из Китая и стран Европы

The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.

Suppression of risk factors including smoking, overdrinking and infections by human papilloma and hepatitis B and C viruses has been recommended for cancer prevention, however, identification of other environmental risk factors has not been enough. Besides the 2003 report that Kawasaki disease may be triggered by pollen exposure, 40 Japanese specific intractable diseases have recently been reported as &ldquo, pollen diseases,&rdquo, also potentially triggered by pollen exposure．Various human organs are affected by pollen exposure, leading to systemic vasculitis, autoimmune connective tissue diseases, inflammatory bowel diseases and intractable neuromuscular and bone diseases, suggesting the common effects of pollen exposure on fundamental functions of vital metabolism. In this context, cancer and malignant tumors may be another group of intractable diseases triggered by epigenetic pollen exposure. Thus, this study compared the number of newly registered patients with 24 types of cancer and airborne pollen levels measured from 1975 to 2015. We searched for statistical correlations with Bonferroni correction between the annual number of newly registered patients for all cancers or for each of lung, stomach, colorectal, pancreatic and breast cancers in the patient-registry year &ldquo, x&rdquo, and annual airborne pollen levels measured in the same year as &ldquo, or 1&ndash, 7 years prior to the year &ldquo, The number of newly registered patients for lung, and pancreatic cancers in the patient-registry year &ldquo, was highly correlated with airborne pollen levels measured 2 years prior to &ldquo, That for breast cancer was correlated with pollen levels measured 2 and 5 years prior to &ldquo, To our knowledge, this is the first rapid communication of the association between pollen levels and cancer incidence.

The purpose of this study was to evaluate cognitive function in patients with multiple sclerosis (MS), compared with control subjects, and to establish whether decline of cognitive function continues in the patients during remission.The Japanese version of the Brief Repeatable Battery of Neuropsychological tests (BRB-N), which includes the selective reminding test (SRT), spatial recall test (SPART), symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), and the word list generation test (WLG), was performed in 34 Japanese patients with MS (8 males, 26 females; mean age, 42 years) and in 37 age- and education-matched healthy controls (20 males, 17 females; mean age, 36 years). BRB-N was conducted at intervals of two years for MS patients who remained in remission, and the cognitive changes were evaluated by comparing the results with those of the initial examination at entry into the study.The MS patients showed lower BRB-N scores than controls, with high significance in the SRT, SRT-D, SDMT and PASAT tests (p0.01). The BRB-N scores of the MS patients who remained in remission were not significantly changed for at least 2 years.The Japanese version of the BRB-N is useful to clarify the nature of cognitive impairment in Japanese MS patients. Based on this neuropsychological assessment, we suggest that working memory and information-processing speed are key deficits. Patients who remained in remission showed little or no further impairment of cognitive functions for at least two years.

Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.

International audience; Objective : Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series.Methods : We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.Results : In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10−3).Interpretation : The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by the expansion of the trinucleotide CAG repeats encoding elongated polyglutamine tract in ataxin-2, the SCA2 gene product. Polyglutamine diseases comprise nine genetic entities, including seven different forms of spinocerebellar ataxias, Huntington's disease, and spinal and bulbar muscular atrophy. These are pathologically characterized by neuronal loss and intranuclear aggregates or inclusions of mutant proteins including expanded polyglutamine in selected neuronal groups. Previously, we examined immunolocalization of ubiquitin, expanded polyglutamine (probed by 1C2 antibody), and ataxin-2 in genetically confirmed SCA2 patients. In the present study, we expanded this approach by distinguishing different patterns of subcellular 1C2 immunoreactivity ("granular cytoplasmic," "cytoplasmic and nuclear" and "nuclear with inclusions.") and by quantifying their regional frequencies in three autopsied SCA2 brains at different stage of the disease. Comparison with neuronal loss and gliosis revealed that overall 1C2 immunoreactivity was paralleled with their severity. Furthermore, appearance of granular cytoplasmic pattern corresponded to early stage, cytoplasmic and nuclear pattern to active stage, and nuclear with inclusions pattern to final stage. We conclude that this 1C2-immunoreactive typing may be useful for evaluating the overall severity and extent of affected regions and estimating the neuropathological stage of SCA2.

Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.

Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of both upper and lower motor neurons. Neuropathologically, degeneration of the corticospinal tracts is evident and may be associated with loss of motor neurons in the motor cortex. The data from a recently developed imaging technology, the diffusion tensor imaging method of MRI have suggested that white matter in the corpus callosum (CC) is lost in patients with ALS. However, the specific neuropathologic changes of the commissural fibers remain unclear. To investigate the pathologic changes of the CC in ALS, we analyzed midsagittal sections of the CC from eight individuals with ALS and eight controls by using conventional staining and immunohistochemistry with antibodies against CD68, GFAP and phosphorylated neurofilament (SMI-31). The CC was divided into seven areas. The number of CD68-immunoreactive macrophages/microglia and GFAP-immunoreactive astrocytes was significantly higher in individuals with ALS than in controls in all areas of the CC except the rostrum. Among the patients with ALS, the number of macrophages/microglia and astrocytes was significantly higher in the posterior midbody and isthmus than in the rostrum. There was no significant difference in number of SMI-31 immunoreactive axons between ALS and control group as well as among each area of the CC. These findings suggest that pathologic changes in the CC in ALS are present in the posterior midbody and isthmus, where callosal motor fibers may traverse between the two hemispheres. CD68 and GFAP immunohistochemistry are sensitive methods to detect those pathologic changes in routine paraffin-embedded specimens.

In neonates, the stress of social isolation can alter developing neural circuits and cause mental illness. However, the molecular and cellular bases for these effects are poorly understood. Experience-driven synaptic AMPA receptor delivery is crucial for circuit organisation during development. In the rat, whisker experience drives the delivery of glutamate receptor subunit 4 (GluA4) but not glutamate receptor subunit 1 (GluA1) to layer 4-2/3 pyramidal synapses in the barrel cortex during postnatal day (P)8-10, whereas GluA1 but not GluA4 is delivered to these synapses during P12-14. We recently reported that early social isolation disrupts experience-driven GluA1 delivery to layer 4-2/3 pyramidal synapses during P12-14. Here, we report that neonatal isolation affects even earlier stages of development by preventing experience-dependent synaptic GluA4 delivery. Thus, social isolation severely affects synaptic maturation throughout early postnatal development.

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias are clinically and genetically heterogeneous disorders with diverse neurological and non-neurological features. We herein describe a Japanese patient with a slowly progressive form of ataxia and spastic paraplegia. Using whole exome sequencing, we identified a novel homozygous frameshift mutation in SPG7, encoding paraplegin, in this patient. This is the first report of an SPG7 mutation in the Japanese population. For disorders previously undetected in a particular population, or unrecognized/atypical phenotypes, exome sequencing may facilitate molecular diagnosis.

Purpose The aim of the present study was to determine the brain regions with altered metabolism in patients with treatment-naive fibromyalgia (FM). Methods We used [18F] fluoro- d -glucose positron emission tomography to examine a total of 18 treatment-naive FM patients and 18 age- and sex-matched healthy controls not suffering from pain. A voxel-by-voxel group analysis was performed using statistical parametric mapping. Results No significant voxel (peak)-level results were detected in this study; however, some regions were detected as significant-size clusters. There were no significant differences in brain metabolism between FM patients and controls. However, the right thalamus and left lentiform nucleus were hypermetabolic areas in FM patients with poor prognosis compared to the healthy controls. In contrast, the left insula and left lentiform nucleus were hypometabolic areas in FM patients with good prognosis compared to the healthy controls. Compared to FM patients with good prognosis, FM patients with poor prognosis showed significant hypermetabolism in the left thalamus, bilateral lentiform nucleus, and right parahippocampal gyrus. Conclusion The present findings suggest an association between the metabolism in the thalamus, lentiform nucleus, and parahippocampal gyrus and prognosis in FM patients. Further study with a larger number of patients is required to confirm this association.

Objective: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. Methods: The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed. Results: The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. Conclusions: The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.

Background: In English- and German-speaking countries, ataxic speech is often described as showing scanning based on acoustic impressions. Although the term ‘scanning’ is generally considered to represent abnormal speech features including prosodic excess or insufficiency, any precise acoustic analysis of ataxic speech has not been performed in Japanese-speaking patients. This raises the question of what is the most dominant acoustic characteristic of ataxic speech in Japanese subjects, particularly related to the perceptual impression of ‘scanning’. Aims: The study was designed to investigate the nature of speech characteristics of Japanese ataxic subjects, particularly ‘scanning’, by means of acoustic analysis. Methods & Procedures: The study comprised 20 Japanese cases with spinocerebellar degeneration diagnosed to have a perceptual impression of scanning by neurologists (ataxic group) and 20 age-matched normal healthy subjects (control group). Recordings of speech samples of Japanese test sentences were obtained from each subject. The recorded and digitized acoustic samples were analysed using ‘Acoustic Core-8’ (Arcadia Inc.). Outcomes & Results: Sentence duration was significantly longer in the ataxic group as compared with the control group, indicating that the speaking rate was slower in the ataxic subjects. Segment duration remained consistent in both vowels and consonants in the control group as compared with the ataxic group. In particular, the duration of vowel segments, i.e. the nucleus of Japanese mora, was significantly invariable in the control group regardless of differences between subjects as well as in segments compared with the ataxic group. In addition, the duration of phonemically long Japanese vowels was significantly shorter in the ataxic group. Conclusions & Implications: The results indicate that the perceptual impression of ‘scanning’ in Japanese ataxic cases derives mainly from the breakdown of isochrony in terms of difficulty in keeping the length of vowel segments of Japanese invariable during speech production. In addition, the tendency toward irregular shortening of the length of phonemically long Japanese vowels is thought to reinforce the impression of ‘scanning’ in ataxic speech in Japanese cases.

A 44-year-old woman was admitted to our hospital with altered mental status and weakness in the left upper and lower limbs. A brain magnetic resonance imaging indicated multiple cerebral infarctions in the bilateral frontal and parietal lobes and in the left occipital lobe. Magnetic resonance angiography indicated overall arterial wall irregularity and stenosis. An electrocardiogram showed negative T waves, troponin I was elevated at 0.60 ng/mL, and an echocardiogram showed severe hypokinesis, leading to a diagnosis of ischemic heart disease; however, no stenosis was found at cardiac catheterization. No other etiology for the angiopathy could be found. Whole-body computed tomography demonstrated an adrenal tumor and urinary catecholamine levels were elevated. Following excision of the adrenal tumor, a diagnosis of pheochromocytoma was made. Postoperatively, the patient's arterial stenosis and cardiac abnormalities improved. It was hypothesized that the patient's cardiomyopathy and vasospasm were secondary to excessive catecholamine secretion from the pheochromocytoma.

Objective To determine the cerebral activity correlated with depth perception of 3-dimensional (3D) images, by recording of human visual evoked potentials (VEPs). Methods Two figures consisting of smaller and larger squares were presented alternately. VEPs were recorded in two conditions. In condition I, we used two figures which yielded flat 2-dimensional images. In condition II, we used two figures which yielded 3D images, which were concave and convex, respectively. Results P1, P2, and N1/P2 amplitude were significantly greater in condition II than in condition I. The P1/N1 amplitude tended to be greater in condition II than in condition I. P1 and N1 were predominantly distributed over the right temporo-parieto-occipital regions. P2 and N2 were distributed over bilateral parieto-occipital regions. Conclusions The difference in P1 amplitude between two conditions can be explained by the difference between conditions, one of which yielded depth perception while the other did not, since previous studies showed that P1 and N1 are modulated by perception of images in depth. The role of P2 and the mechanism responsible for the increase in P2 amplitude during condition II remain unknown. Significance We recorded VEPs and identified electrophysiological correlates of depth perception with 3D images produced by concave/convex figures.

The type and frequency of neurological manifestations of Behçet's disease (BD) vary with ethnicity. We analyzed the neurological manifestations of BD in Japanese patients. All patients undergoing treatment at one of the two Yokohama City University hospitals from July 1991 to December 2007 and who fulfilled the Japanese criteria for BD revised in 1987 were studied retrospectively by chart review. Patients had been neurologically assessed by neurologists. We recorded neurological signs and symptoms, magnetic resonance imaging or computed tomography findings, and results of cerebrospinal fluid examinations from the records of each patient. We studied 412 patients with BD, of whom 54 (13%) had neurological involvement (neuro-Behçet's disease: NB). NB patients included a significantly higher proportion of males (61%) than non-NB patients (42%, P = 0.009). The majority of patients (n = 38, 70%) had acute parenchymal NB, 15 (28%) had chronic progressive parenchymal NB, and 1 (2%) had the non-parenchymal type. Headache and fever were more frequently reported by patients with acute parenchymal NB. Personality changes, sphincter disturbances, involuntary movements, and ataxia occurred predominantly in patients with chronic progressive parenchymal NB. Lesions were distributed throughout the CNS, but mainly in the brainstem, white matter, and basal ganglia. Analysis of end-point clinical outcomes revealed a poor prognosis for patients with chronic progressive NB. In Japan, most NB patients have the parenchymal type, and male gender is a predisposing factor. Because of the unfavorable prognosis associated with chronic progressive NB, development of effective therapies are urgently needed.

症例は30歳，男性．特記すべき既往歴や家族歴はない．某日夜から朝にかけて大量に飲酒，仮眠を取った後，頭痛および左口唇周囲のしびれ感を自覚，左片麻痺を発症した．頭部MRIにて右中脳腹側に脳梗塞を認め脳幹梗塞と診断した．MRAでは特記すべき異常を認めなかった．脳梗塞の原因検索を行ったが，血管炎，凝固異常，心原性塞栓や奇異性塞栓を示唆する所見はなかった．脳血管撮影で，右椎骨動脈に窓形成を認め，脳梗塞の原因は窓形成部からの塞栓症と考えた．窓形成による脳梗塞の報告は少ないが，原因の特定できない脳梗塞では脳血管撮影まで含めた精査が必要なことが示唆された．

We report a 50-year-old woman with an unremarkable birth and developmental history, and with no family history of neurological disorders. The patient had a 6-year history of progressive cervical dystonia, oral dyskinesia, and hyperreflexia. She was initially considered to have spastic paraparesis of unknown cause. Because brain MRI showed mild atrophy of the cerebellar vermis, genetic analysis for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, and 17, and dentatorubral-pallidoluysian atrophy was performed. The results revealed an abnormal expansion of CAG repeats (38 repeats) in one allele of ATXN2, and the patient was diagnosed with spinocerebellar ataxia type 2 (SCA2). She had no major clinical features of SCA2 such as cerebellar ataxia, slow saccade, or hyporeflexia. Recent reports have shown the CAG repeat expansion in ATXN2 to be detected in patients with familial L-dopa-responsive parkinsonism. The present case suggests that CAG repeat expansion in ATXN2 may be detected in some patients with spastic paraparesis, and that wide variations of clinical manifestations exist in SCA2.

A 65-year-old man developed progressive worsening of right-sided limb-kinetic apraxia and extrapyramidal dysfunction. His left internal carotid artery was found to be occluded, and there was general atrophy and severely decreased cerebral blood flow in the left hemisphere. He had experienced an acute infarction in the left watershed area before superficial temporal artery to middle cerebral artery bypass surgery. After surgery, the cerebral blood flow in the left hemisphere was remarkably improved. Unilateral internal carotid artery occlusion may result in clinical manifestations similar to corticobasal degeneration.

Objective We previously reported on vitamin E malabsorption after gastrectomy. In this study, we focused on neurological dysfunction due to serum vitamin E decrease during the postgastrectomy period in lager number of patients. Methods We examined the type of gastrectomy, type of reconstruction, serum vitamin E level, and neurological status for 96 gastrectomy patients. Results Low serum vitamin E levels were observed in 20 patients, and 10 of those patients suffered some neurological symptoms, i.e., peripheral neuropathy, limb or truncal ataxia. Vitamin E levels tended to decrease with time after gastrectomy, and the number of patients with low serum vitamin E levels increased at about 50 months after gastrectomy. This relationship was stronger in total gastrectomy patients than in subtotal gastrectomy patients. Ten patients were given oral vitamin E, and serum vitamin E levels normalized in 9 of the patients and neurological abnormalities improved in 8 patients. An oral intake of 300 mg or more of vitamin E was necessary for normalization of vitamin E levels. Conclusions Gastrectomy should be considered a risk for vitamin E deficiency and neurological disturbance over the long-term clinical course. An oral vitamin E supply can improve serum vitamin E levels and neurological symptoms.

Infarction in the genu of the internal capsule causes dementia that is characterized by abulia, lethargy and memory loss without obvious motor palsy (capsular genu syndrome). We found infarction or decreased cerebral blood flow in the genu of the internal capsule in 6 of 13 patients with severe bacterial meningitis. Four of these six patients developed post-meningitis dementia, characterized by abulia, lethargy, and memory loss. Of 24 patients with viral meningitis, none developed capsular genu ischemia or post-meningitis dementia. In patients with severe bacterial meningitis, capsular genu ischemia may play some role in the development of post-meningitis dementia. In patients with viral meningitis, absence of such ischemia may explain, at least in a part, the rarity of post-meningitis dementia.

成人肺炎球菌性髄膜炎に伴う脳梗塞において，MR angiography（MRA）で可逆性脳動脈狭窄を確認しえた症例を経験したので報告する．症例は74歳，男性．発熱，意識障害を認め当科に入院し肺炎球菌性髄膜炎と診断された．入院14日目のMRI検査では脳幹・両側大脳半球に多発梗塞像を認めMRAで両側中・後大脳動脈，脳底動脈の壁不整，狭窄像を認めた．入院39日目にはMRAで脳動脈狭窄の改善を認め，狭窄が可逆的であったことを確認した．本症例は細菌性髄膜炎に伴う脳動脈狭窄，脳梗塞の機序に血管攣縮が関与していることを示唆する貴重な症例と考えられた．細菌性髄膜炎に伴う脳動脈血管炎，脳梗塞の合併は予後を悪化させる因子であるにもかかわらず，現在までにその予防法，治療法は確立されていない．今後，細菌性髄膜炎に伴う脳動脈血管炎，脳梗塞の有効な予防法・治療法を検討する上で，MRAの観察は重要であると考えられた．

Recent studies demonstrated an altered P3 component and prolonged reaction time during the visual discrimination tasks in multiple system atrophy (MSA). In MSA, however, little is known about the N2 component which is known to be closely related to the visual discrimination process. We therefore compared the N2 component as well as the N1 and P3 components in 17 MSA patients with these components in 10 normal controls, by using a visual selective attention task to color or to shape. While the P3 in MSA was significantly delayed in selective attention to shape, the N2 in MSA was significantly delayed in selective attention to color. N1 was normally preserved both in attention to color and in attention to shape. Our electrophysiological results indicate that the color discrimination process during selective attention is impaired in MSA.

症例は76歳男性．重度の意識障害（JCSIII-200）と右片麻痺を発症して入院した．頭部CT検査で左側の被殻から前頭葉にかけて著明な正中構造偏倚を伴う血腫を認め，左被殻出血と診断した．入院時の神経学的所見で右側への眼球共同偏倚と右眼の瞳孔散大が合併し，責任病巣の推定が困難であった． 脳MRI検査を行ったところ，正中構造偏倚に伴う中脳の右側への歪曲と右傍正中領域の梗塞巣を認めた．被殼出血における病初期の対側瞳孔散大はまれな症候で，病態も不明な点が多いが，血腫の圧排による対側中脳梗塞が原因となる場合があることを報告した．

An 83-year-old woman developed high fever and headache for four days. She had disturbance of consciousness and was admitted to our hospital. A lumbar puncture was performed and cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 268/mm3 and culture became positive for Listeria monocytogenes. Six days after admission, the adenosine deaminase (ADA) level in CSF markedly elevated (43.3 IU/L) with pleocytosis, but a negative PCR test for tuberculosis in CSF, sputum, gastric fluid. She recovered by antibiotics for 45 days and ADA level in CSF was normalized. She was diagnosed as listeria meningitis. High levels of ADA in CSF have high sensitivity and high specificity for tuberculous meningitis, but there are some reports that high ADA levels in CSF in other meningitis. The main biological role of ADA is related to proliferation and differentiation of lymphocytes, and specific activity of this enzyme is slightly higher in T-lymphocytes than in B-lymphocytes. Protective immunity to Listeria monocytogenes is exclusively exhibited by T-lymphocytes. We consider that increased ADA levels in listeria meningitis associated with elevation of T-lymphocytes in CSF. This report suggests that listeria meningitis must be included in the differential diagnosis of high levels of ADA in CSF.

Formation of intracellular aggregates is the hallmark of polyglutamine (polyQ) diseases. We analyzed the components of purified nuclear polyQ aggregates by mass spectrometry. As a result, we found that the RNA-binding protein translocated in liposarcoma (TLS) was one of the major components of nuclear polyQ aggregate-interacting proteins in a Huntington disease cell model and was also associated with neuronal intranuclear inclusions of R6/2 mice. In vitro study revealed that TLS could directly bind to truncated N-terminal huntingtin (tNhtt) aggregates but could not bind to monomer GST-tNhtt with 18, 42, or 62Q, indicating that the tNhtt protein acquired the ability to sequester TLS after forming aggregates. Thioflavin T assay and electron microscopic study further supported the idea that TLS bound to tNhtt-42Q aggregates at the early stage of tNhtt-42Q amyloid formation. Immunohistochemistry showed that TLS was associated with neuronal intranuclear inclusions of Huntington disease human brain. Because TLS has a variety of functional roles, the sequestration of TLS to polyQ aggregates may play a role in diverse pathological changes in the brains of patients with polyQ diseases.

A-58-year old man presented with fluctuating ptosis and dysphagia. When he was 53 years old, he developed oral candidiasis and serum human immunodeficiency virus (HIV) RNA was detected. After starting highly active antiretroviral therapy, serum HIV RNA became undetectable. Neurological examination revealed ptosis and bulbar symptoms. Myasthenia gravis was comfirmed by a positive edrophonium test, showing 20% decrement of the compound muscle action potential on repetitive stimulation. Anti-acetylcholine receptor antibodies were negative and anti-muscle specific tyrosine kinase (MuSK) antibodies were positive. The chest CT scan was normal. He experienced transient clinical remission with pyridostigmine bromide and prednisolone. However relapse occurred after he returned to work. Persistent clinical remission was first observed after cyclosporin administration. There are eleven reports in which patients had concomitant myasthenia gravis and HIV infection. Most of those cases were benign in clinical course and required only anticholinesterase therapy. In our case, however, anti-MuSK antibodies were positive, and symptoms of myasthenia gravis remained despite prednisolone administration. Cyclosporin is directly active against HIV, and thus, cyclosporine therapy may be helpful in patients with concomitant myasthenia gravis and HIV infection.

Fig 1 is an incorrect, previous version. Please view the corrected Fig 1 here. Fig 1 A diagram of the assumptions underlying the present analysis.

A 19-year-old female patient, who had exhibited esotropia, mild cerebellar ataxia, mild mental retardation, and cerebellar atrophy on magnetic resonance images at the age of 15, developed signs of acute encephalopathy, and thereafter died of disseminated intravascular coagulation on the day of her admission. Both her mother and sister suffered from attacks of hemiplegic migraine, mild mental retardation, and cerebellar ataxia. Neuropathological examinations revealed acute changes in the widespread cerebral cortex, chronic degenerative changes in the anterior lobe of the cerebellar vermis, axonal spheroids in the Goll's nucleus, pseudo-calcinosis in the globus pallidus, and glial bundles in the cranial nerves. The most fascinating features were changes of Purkinje cells, such as cactuses (asteroid bodies, dendritic expansions), somatic sprouts, and torpedoes. These changes may be characteristic of familial hemiplegic migraine with cerebellar atrophy, as well as the other metabolic diseases, such as Menkes' kinky hair disease, infantile (Tay-Sachs type) amaurotic idiocy, organic mercury intoxication, and mitochondrial encephalopathy, of which cases often exhibit such pathological changes of Purkinje cells. Therefore, familial hemiplegic migraine may share some metabolic abnormalities with the diseases mentioned above.

Background: Relationships between impairment, disability and handicap in neurological diseases such as stroke and spinal cord injury have been studied using the framework of the international classification of impairment, disability and handicap, defined by World Health Organization. Those relationships in Parkinson's disease have rarely been studied on a statistical basis. Methods: In order to identify relationships between impairment, disability, handicap, burden of care, economic expenses and neurophysiological dysfunction in patients with Parkinson's disease, we made quantitative evaluations of these parameters in 24 patients and 14 care-givers. Impairment was measured by symptomatic assessment for motor and autonomic impairments and neuropsychological assessment using the revised version of Hasegawa's dementia scale, the mini-mental state examination, and the self-rating depression scale. Disability was measured by Hoehn and Yahr scale, Barthel index, and the comprehensive activities of daily living index for the elderly. Handicap was measured by the Craig handicap assessment and reporting technique. Scores for burdens of care on principal care-givers had physical and psychosocial aspects. Neurophysiological dysfunction was studied by measuring visual event-related potentials and regional cerebral blood flow. Results: Motor and cognitive impairments, disability and handicap significantly correlated to each other. In particular, disability and handicap were strongly correlated. The burden of care on care-givers, economic expenses, visual event-related potentials and regional cerebral blood flow were significantly correlated with impairment, disability and handicap. Conclusion: Further investigations are anticipated to confirm practical values of symptomatic, neuropsychological, electrophysiological and neuroimaging evaluations to predict burden of care on families and economic expenses for patients with Parkinson's disease.

We have introduced S1–S2 paradigm (task S) as well as oddball paradigm (task O) visual event-related potentials (ERPs) under different interstimulus intervals (ISIs) in Parkinson's disease (PD). ERP measurements were correlated with motor disability, WAIS-R, and regional cerebral blood flow (rCBF). The ‘group’ influence was characterized by longer latency for P300, N200, and reaction time and decreased P300 amplitude in PD. Both P300 latency and reaction time during task O showed significantly longer latency in longer ISI condition. Our results revealed ‘ISI’ influence on ERPs during task S and significant correlation between ERPs and rCBF in task S.

We studied the differences in latency and amplitude between the laser stimulated visual evoked potentials (VEPs) and the cathode-ray tubes (CRTs) stimulated VEPs to estimate the risk of inducing photosensitive epilepsy by laser displays. Twenty healthy subjects were recruited for the study. Red and blue light stimulations were flashed in 1, 7.5 and 15Hz. The latency of P1, N1, P2 and N2 in 1 Hz stimulation revealed no significant difference by a paired t test between laser and CRT stimulation. The peak-to-peak amplitude was significantly smaller with red or blue laser stimulation than with red or blue CRT stimulation, for PI-N1 and N1-P2 at 7.5Hz stimulation, and for N1-P2 and P2-N2 at 15Hz stimulation. We therefore postulate that laser does not produce more excitability to occipital cerebral cortex than CRT does. There was no evidence to say that laser stimulation is more dangerous as the risk of inducing photosensitive epilepsy than conventional CRT stimulation.

すくみ足は,歩行障害の一種で,パーキンソン病及びパーキンソン症候群に認められる症候の一つであるが,他のパーキンソン症候と異なる性質と病態で出現すると推測されている.そこで,外来受診中のすくみ足を伴う症例の画像所見を解析し,その責任病巣について検討した.その結果,すくみ足症例に高率に前頭葉病変が認められ,今まで報告のある前頭葉由来の仮説が裏付けられた.このことから,すくみ足治療は,前頭葉機能に注目して行うことが有用であると考えられた., Although it is known that frozen gait is a symptom of Parkinson's disease (PA), it has not been fully studied in a variety of other diseases with parkinsonian syndrome, such as vascular parkinsonism, normal pressure hydrocephalus (NPH), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy. The present study was conducted to investigate whether common abnomalies of brain CT or MRI exist in patients with frozen gait. The subjects were of 7 patients with PA, 9 patients with stroke, 5 patients with both PA and stroke, 2 CBD patients, 1 PSP patient, and 1 NPH patient. Frontal white matter lesions were observed in 13 (93%) of 14 patients with PA or PA and stroke. Frontal lobe atrophy was observed in 5 (70%) of 7 patients with PA. Dysartheic disorders were associated in 6 (24%) of 25 patients with frozen gait. Since it is thought that frozen gait is a motor symptom related to frontal lobe dysfunction, the treatment of frozen gait might be conducted by improving frontal lobe function.