記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In this randomized, double-blind, placebo-controlled study, we investigated the effects of collagen peptides (CP) containing high concentrations of prolyl-hydroxyproline and hydroxyprolyl-glycine on the advanced glycation end products (AGEs) levels in the skin and subcutaneous blood vessel walls. Thirty-one individuals aged 47-87 years were randomly assigned to receive either 5 g/day fish-derived CP or a placebo for 12 weeks. Body and blood compositions and AGEs levels were measured at the beginning and end of the study. No adverse events were observed, and both groups' blood and body compositions did not change significantly. However, the CP group had significantly lower AGEs levels and a slightly lower insulin resistance index (HOMA-R) than the placebo group. In addition, the % changes in AGEs and HOMA-R levels were positively and strongly correlated in both groups. These findings suggest that fish-derived CP may be effective in reducing AGEs levels and improving insulin resistance.

DOI： 10.1093/bbb/zbad065

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(公社)日本リハビリテーション医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Identifying plasma molecules associated with skeletal muscle properties can elucidate the pathophysiology of sarcopenia. Because adipocytokines are a promising candidate marker, the current study aimed to clarify the possible associations between adiponectin and leptin levels and mid-thigh muscle cross-sectional area and mean attenuation value, which are indices of muscle mass and fat deposition in muscle, respectively. METHODS: The current study included 1440 older Japanese adults (mean age 69.3 years). Mid-thigh skeletal muscle cross-sectional area and mean attenuation value were evaluated through computed tomography scan. A low attenuation value showed a greater fat deposition in muscle. Circulating adiponectin and leptin levels were assessed using blood specimens collected during the baseline investigation. RESULTS: Plasma leptin level was inversely correlated with muscle cross-sectional area, but not with attenuation value. The association with cross-sectional area was independent of possible confounding factors including body size (Q1: reference; Q2: β = -0.032, P = 0.033; Q3: β = -0.064, P < 0.001; Q4: β = -0.111, P < 0.001). In contrast, adiponectin level was independently and inversely associated with attenuation value (Q1: reference; Q2: β = -0.044, P = 0.122; Q3: β = -0.080, P = 0.006; Q4: β = -0.159, P < 0.001), but not with cross-sectional area. These associations between adipocytokine levels and muscle properties were independent of abdominal fat area and insulin resistance. CONCLUSIONS: There were adiposity- and insulin resistance-independent associations between adipocytokines levels and skeletal muscle mass and fat deposition in muscle, suggesting an involvement of adipocytokines in muscle properties. Geriatr Gerontol Int 2023; ••: ••-••.

DOI： 10.1111/ggi.14582

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: Phase angle (PhA) calculated from the resistance and reactance measured using a bioimpedance device was suggested to represent the degree of fat deposition in muscle (myosteatosis), though no direct evidence is available. We aimed to clarify the possible association between PhA and skeletal muscle myosteatosis in community-dwelling middle-aged to older adults. METHODS: Participants consisted of 424 Japanese (aged ≥50 years). Leg PhA and skeletal muscle mass index (SMI) were obtained by bioelectrical impedance analysis. The mean attenuation values and cross-sectional area of the mid-thigh skeletal muscle were calculated from computed tomography images and considered as indexes of myosteatosis and skeletal muscle mass, respectively. RESULTS: Leg PhA was positively associated with SMI, and cross-sectional area and mean attenuation value at mid-thigh. Multiple regression analysis adjusted for possible covariates identified leg PhA (β = 0.214) and SMI (β = 0.260) as independent factors of mid-thigh muscle cross-sectional area (P < 0.001), while leg PhA (β = 0.349, P < 0.001) but not SMI (P = 0.645) was associated with mean attenuation value. Similar results were observed in the analysis in the older (≥65 years) subpopulation. The combination of low SMI and low leg PhA showed stepwise association with cross-sectional area, while only individuals with low leg PhA had lower mean attenuated value. CONCLUSIONS: Leg PhA was independently associated with mean attenuated value of the mid-thigh skeletal muscle, suggesting that the assessment of PhA in combination with SMI could provide additional information for the evaluation of muscle properties.

DOI： 10.1016/j.clnu.2023.03.016

PubMed

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記述言語：英語  

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be "damaging" by PolyPhen-2 and "deleterious" using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.

DOI： 10.3389/fgene.2023.1155998

PubMed

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記述言語：日本語   出版者・発行元：愛媛医学会  

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

The rapid aging of the population makes the detection and prevention of frailty increasingly important. Oral frailty has been proposed as a novel frailty phenotype and is defined as a decrease in oral function coexisting with a decline in cognitive and physical functions. Oral frailty has received particular attention in relation to Alzheimer's disease (AD). However, the pathomechanisms of oral frailty related to AD remain unknown. It is assumed that the mesencephalic trigeminal nucleus (Vmes), which controls mastication, is affected by AD pathology, and as a result, masticatory function may be impaired. To investigate this possibility, we included male 3 × Tg-AD mice and their non-transgenic counterpart (NonTg) of 3–4 months of age in the present study. Immunohistochemistry revealed amyloid-β deposition and excessive tau phosphorylation in the Vmes of 3 × Tg-AD mice. Furthermore, vesicular glutamate transporter 1-immunopositive axon varicosities, which are derived from Vmes neurons, were significantly reduced in the trigeminal motor nucleus of 3 × Tg-AD mice. To investigate whether the AD pathology observed in the Vmes affects masticatory function, we analyzed electromyography of the masseter muscle during feeding. The 3 × Tg-AD mice showed a significant delay in masticatory rhythm compared to NonTg mice. Furthermore, we developed a system to simultaneously record bite force and electromyography of masseter, and devised a new method to estimate bite force during food chewing in mice. Since the muscle activity of the masseter showed a high correlation with bite force, it could be accurately estimated from the muscle activity. The estimated bite force of 3 × Tg-AD mice eating sunflower seeds was predominantly smaller than that of NonTg mice. However, there was no difference in masseter weight or muscle fiber cross-sectional area between the two groups, suggesting that the decreased bite force and delayed mastication rhythm observed in 3 × Tg-AD mice were not due to abnormality of the masseter. In conclusion, the decreased masticatory function observed in 3 × Tg-AD mice was most likely caused by AD pathology in the Vmes. Thus, novel quantitative analyses of masticatory function using the mouse model of AD enabled a comprehensive understanding of oral frailty pathogenesis.

DOI： 10.3389/fnagi.2022.935033

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記述言語：英語   出版者・発行元：(一社)日本脳神経超音波学会  

下顎窓から測定した、内頸動脈(ICA)における脳血管反応性(CVR)診断の有用性について検討した。有効な側頭窓が確認された健常者25例(男性13例、女性12例、平均年齢39.9±13.7歳)を対象に、息こらえ試験を行い、CVR指標としてbreath holding index(BHI)を用い、息こらえ前後の平均血流速度からBHIを算出し、ICAで測定したBHI(BHIi)と同側中大脳動脈で測定したBHI(BHIm)との相関性を評価した。その結果、BHImおよびBHIiはそれぞれ平均0.93±0.29および平均0.92±0.32で、BHImとBHIiのSpearman相関係数は0.665であった。また、BHImにより決定されたCVR障害に対するBHIiのカットオフポイントは0.71で、感度と特異度はともに80%得られた。以上の結果から、側頭窓からの測定が不十分である場合には、下顎窓からのBHI測定が代替測定として有用であることが明らかにされた。

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J02558&link_issn=&doc_id=20220113570003&doc_link_id=%2Fcn7neuro%2F2021%2F003403%2F003%2F0142-0147%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcn7neuro%2F2021%2F003403%2F003%2F0142-0147%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.msard.2021.103135

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background We assessed cases of incidental unruptured intracranial aneurysm (UIA) discovered on screening magnetic resonance angiography to identify hemodynamic and atherosclerotic risk factors. Methods and Results The data of 1376 healthy older subjects (age range, 31-91 years) without cerebro- or cardiovascular diseases who underwent brain magnetic resonance angiography as part of a medical checkup program at a health screening center were examined retrospectively. We looked for an increase in classical risk factors for UIAs (age, sex, hypertension, and smoking) and laboratory data related to lifestyle diseases among subjects with UIAs. Brachial-ankle pulse wave velocity, central systolic blood pressure, radial augmentation index, and carotid flow pulsatility index were also compared between those with and without UIAs. We found UIAs in 79 (5.7%) of the subjects. Mean age was 67.1±9.0 years, and 55 (70%) were women. Of the 79 aneurysms, 75 (95%) were in the anterior circulation, with a mean diameter of 3.1 mm (range, 2.0-8.0 mm). Subjects with UIAs were significantly older and had more severe hypertension. The carotid flow pulsatility index was significantly lower in subjects with UIAs and negatively and independently correlated with UIAs. Tertile analysis stratified by carotid flow pulsatility index revealed that subjects with lower indices had higher levels of low-density lipoprotein cholesterol. Conclusions The presence of UIAs correlated with lower carotid flow pulsatility index and elevated low-density lipoprotein cholesterol in the data from a population of healthy older volunteers. A reduced carotid flow pulsatility index may affect low-density lipoprotein cholesterol elevation by some molecular pathways and influence the development of cerebral aneurysms. This may guide aneurysm screening indications for institutions where magnetic resonance angiography is not routine.

DOI： 10.1161/JAHA.120.018626

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jamda.2021.06.033

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記述言語：日本語   出版者・発行元：日本脳神経超音波学会・日本栓子検出と治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

DOI： 10.1038/s41588-021-00852-9

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.ensci.2021.100346

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Sarcopenia is a risk factor for poor outcomes in older adults. Identification of plasma markers may facilitate screening of sarcopenia. We previously reported that creatinine-to-cystatin C ratio is a simple marker of muscle mass. To further assess the clinical relevance of the creatinine-to-cystatin C ratio, we investigated its association with myosteatosis and physical performance. DESIGN: Observational study. SETTING AND PARTICIPANTS: Cross-sectional analysis of the dataset obtained from a Japanese population consisting of 1468 older (≥60 years of age) community residents. METHODS: The mean attenuation values of the skeletal muscle calculated from computed tomography images of the midthigh were used as an index of myosteatosis, while the cross-sectional area of the muscle was used as a proxy for muscle mass. Physical performance was assessed by 1-leg standing time. RESULTS: Creatinine-to-cystatin C ratio was positively associated with the cross-sectional area of muscle fiber-rich muscles, while it showed an inverse association with fat-rich muscle areas, resulting in the positive association between creatinine-to-cystatin C ratio and the mean attenuation value of the skeletal muscle [creatinine-to-cystatin C ratio quartiles (Q), Q1: 47.4 ± 4.8, Q2: 48.9 ± 4.4, Q3: 49.8 ± 4.1, Q4: 50.9 ± 3.7, P < .001]. The results of the linear regression analysis adjusted for major covariates (including muscle cross-sectional area) identified creatinine-to-cystatin C ratio as an independent determinant of the mean attenuation value (Q1: reference, Q2: β = 0.07, P = .019, Q3: β = 0.11, P < .001, Q4: β = 0.16, P < .001). Low creatinine-to-cystatin C ratio was independently associated with 1-leg standing time, although the association was attenuated substantially by adjusting for skeletal muscle cross-sectional area and mean attenuation value. CONCLUSION AND IMPLICATIONS: Creatinine-to-cystatin C ratio was associated with myosteatosis in older adults, independent of the muscle mass. Creatinine-to-cystatin C ratio may serve as a convenient marker of sarcopenia.

DOI： 10.1016/j.jamda.2021.03.021

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Glomus tumors are soft tissue neoplasms comprised of glomus cells, vasculature, and smooth muscle cells, which occur commonly in a single subungual area of the digits, and their main clinical features include severe paroxysmal pain, localized tenderness, and cold hypersensitivity. CASE PRESENTATION: A 47-year-old Japanese man had suffered from chronic progressive paroxysmal shooting pain in his right leg since childhood. He avoided putting weight on his right foot whenever he walked. The frequency of paroxysmal pain and the number of tender points both gradually increased with age, and his right leg gradually atrophied. Magnetic resonance imaging of the lower extremity demonstrated multiple gadolinium-enhanced nodules that corresponded with his tender points. Excisional biopsy relieved his pain and provided a histopathological diagnosis of glomus tumors. CONCLUSION: This case suggests that small glomus tumors located in deep tissue may cause disuse atrophy because of their long delay before diagnosis. Clinicians should consider the potential for glomus tumors when patients exhibit unilateral lower limb muscular atrophy with pain.

DOI： 10.1186/s13256-020-02616-1

PubMed

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：英語  

We describe a 61-year-old woman with bilateral parkinsonism caused by unilateral infarction limited to the territory of the lenticulostriate arteries. Although dopamine transporter imaging with single-photon emission computed tomography (DaTSPECT) demonstrated reduced putaminal tracer binding concordant with the size and location of the vascular lesion, the specific binding ratio was within the normal range. Five months after onset, the patient was free from parkinsonism without the use of any antiparkinsonian agents. When patients show bilateral parkinsonism, it is important to consider infarction of the lenticulostriate arteries. Additionally, DaTSPECT might be useful for predicting the prognosis of parkinsonism caused by infarction.

DOI： 10.1016/j.ensci.2020.100291

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(株)中外医学社  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Casein hydrolysate has been shown to improve arterial stiffness as estimated by brachial-ankle pulse wave velocity (baPWV) in untreated hypertensive patients. Facial pigmentation is associated with atherosclerosis, both of which are supposed to be modulated by tissue accumulation of advanced glycation end products (AGEs). However, effects of casein hydrolysate on facial pigmentation and AGEs remain largely unknown. This randomized double-blind placebo-controlled trial evaluated whether and how casein hydrolysate improves facial pigmentation in 80 nonhypertensive Japanese patients. Study participants were randomly assigned to receive either active tablets containing casein hydrolysate or placebo for 48 weeks. Facial pigmentation area, baPWV, and skin accumulation levels of AGEs were evaluated by Robo Skin Analyzer RSA50S II, volume-plethysmographic apparatus, and AGE Reader, respectively, at baseline and at the end of the intervention. Treatment with casein hydrolysate, but not placebo significantly reduced triglycerides and facial pigmentation area. There were significant differences of changes in triglycerides, facial pigmentation area, skin accumulation levels of AGEs, and baPWV between the two groups. Furthermore, changes in triglycerides and skin accumulation levels of AGEs were positively and independently associated with those in facial pigmentation area, whereas changes in baPWV were not. This study suggests that casein hydrolysate reduces facial pigmentation area in nonhypertensive participants partly by decreasing skin accumulation levels of AGEs. Clinical-Trials.gov ID: UMIN000027675.

DOI： 10.1089/rej.2020.2343

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Sarcopenia increases mortality risk in older adults. Loss of skeletal muscle mass is a cardinal feature of sarcopenia. The creatinine-to-cystatin C ratio (CCR) has been suggested as a marker of muscle mass. The present study investigated the usefulness of CCR in discriminating the risk of low muscle mass and weak muscle strength in an elderly population. METHODS: The present cross-sectional study included 1,329 apparently healthy community residents aged 60 years or older. The cross-sectional area (CSA) of muscle in the mid-thigh was measured using computed tomography. Clinical data recorded at routine medical check-ups were obtained from each participant's medical record. RESULTS: Mean muscle CSA was 109 ± 24 cm2. CCR by quartiles according to sex was strongly associated with muscle CSA (Q1: 104 ± 22, Q2: 108 ± 24, Q3: 110 ± 23, and Q4: 114 ± 25 cm2, F = 10.38, P < 0.001). This association was independent of major covariates (Q1: reference, Q2: β = 0.06, P < 0.001, Q3: β = 0.10, P < 0.001, and Q4: β = 0.17, P < 0.001) even in a sex-separated analysis. Although creatinine alone was independently associated with muscle CSA (F = 5.81, P < 0.001), the association was weaker than that of CCR, particularly in the individuals with renal functional decline. Also, CCR was associated with grip strength independently of muscle CSA. CONCLUSION: CCR was a simple marker of low muscle mass and weak muscle strength in older community-dwelling adults.

DOI： 10.1016/j.clnu.2019.07.027

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = -0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

DOI： 10.1016/j.nbd.2020.104739

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Serdi-Editions  

Objectives: To clarify whether serum creatinine to cystatin C ratio (CCR), a marker of muscle mass and muscle function may be used as a simple marker of bone property. Design: A cross-sectional analysis. Setting: A general population-based observation study. Participants: 1,606 middle-aged to elderly (≥50 years, mean age: 66.9 ± 7.5 years old) men (n = 642) and post-menopausal women (n = 964). Measurement: Speed of sound (SOS) at the calcaneal bone was used as a surrogate marker of bone mineral density. The cross-sectional area of the muscle at the mid-thigh was measured using computed tomography. Results: There was significant linear correlation between the quartiles of CCR and SOS (Q1: 1,495 ± 25, Q2: 1,499 ± 24, Q3: 1,507 ± 26, Q4: 1,511 ± 25 m/sec
P &lt
0.001) even in a sex-separated analysis. This association was independent of major covariates (Q1: β = −0.126, P &lt
0.001
Q2: β = −0.096, P = 0.001
Q3: β = −0.022
P = 0.412, Q4: reference) and the mid-thigh muscle mass, while creatinine alone or eGFR did not show clear association with SOS. Conclusion: The CCR may be used as a simple marker of bone property independently of muscle mass in a general population with preserved renal function.

DOI： 10.1007/s12603-020-1315-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant neurodegenerative disorder caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We, herein, report the first Japanese case of ALSP caused by a de novo p.Phe849del mutation in CSF1R: a 44-year-old man who presented callosal disconnection symptoms. Brain MRI revealed dilation of the lateral ventricles, periventricular white matter hyperintensities, and thinning of the corpus callosum with hyperintensities on T2-weighted and FLAIR images. Brain single photon emission computed tomography (SPECT) showed hypoperfusion in the anterior corpus callosum. White matter lesions in MRI and hypoperfusion in SPECT increased with age. A brain biopsy at 44 years revealed axonal spheroids. Callosal disconnection symptoms and hypoperfusion in the anterior corpus callosum may be important indicators of ALSP, especially when caused by a p.Phe849del CSF1R mutation.

DOI： 10.1111/ncn3.12367

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The mesencephalic trigeminal nucleus (Vmes) is not only anatomically adjacent to the locus coeruleus (LC) but is also tightly associated with the function of the LC. The LC can be the first area in which Alzheimer's disease (AD) develops, although it is unclear how LC neuronal loss occurs. OBJECTIVE: We investigated whether neuronal death in the Vmes can be spread to adjacent LC in female triple transgenic (3×Tg)-AD mice, how amyloid-β (Aβ) is involved in LC neuronal loss, and how this neurodegeneration affects cognitive function. METHODS: The molars of 3×Tg-AD mice were extracted, and the mice were reared for one week to 4 months. Immunohistochemical analysis, and spatial learning/memory assessment using the Barnes maze were carried out. RESULTS: In 4-month-old 3×Tg-AD mice, aggregated cytotoxic Aβ42 was found in granules in Vmes neurons. Neuronal death in the Vmes occurred after tooth extraction, resulting in the release of cytotoxic Aβ42 and an increase in CD86 immunoreactive microglia. Released Aβ42 damaged the LC, in turn inducing a significant reduction in hippocampal neurons in the CA1 and CA3 regions receiving projections from the LC. Based on spatial learning/memory assessment, after the tooth extraction in the 4-month-old 3×Tg-AD mice, increased latency was observed in 5-month-old 3×Tg-AD mice 1 month after tooth extraction, which is similar increase of latency observed in control 8-month-old 3×Tg-AD mice. Measures of cognitive deficits suggested an earlier shift to dementia-like behavior after tooth extraction. CONCLUSION: These findings suggest that tooth extraction in the predementia stage can trigger the spread of neurodegeneration from the Vmes, LC, and hippocampus and accelerate the onset of dementia.

DOI： 10.3233/JAD-200257

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.24659/gsr.6.2_75

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, Alzheimer's disease (AD) is understood as "diabetes of the brain" or "type 3 diabetes." Recent clinical trials of anti-amyloid β-protein (Aβ) therapies have not proved to be successful. Thus, glucose-insulin metabolism in the brain is thought to be an alternative therapeutic target. Various types of antidiabetic drugs such as insulin, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, biguanides, and others have been reported to be effective on cognitive impairment in animal models and patients with DM or AD. Here, recent reports are reviewed. While we identified apomorphine (APO) as a novel drug that promoted intracellular Aβ degradation and improved memory function in an AD mouse model, more recently, we have revealed that APO treatment improves neuronal insulin resistance and activates insulin-degrading enzyme (IDE), a major Aβ-degrading enzyme. In this context, recovery of impaired insulin signaling in AD neurons may be a promising therapeutic strategy for AD dementia.

DOI： 10.1007/978-981-13-3540-2_11

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Favorable effects of sauna bathing on cardiovascular disease have been demonstrated. Hot water bathing is an alternative, and could also have similar effects. Information pertaining to hot water bathing frequency and water temperature was obtained from 873 subjects. Carotid mean and max intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured as indices of atherosclerosis. Central haemodynamics were evaluated using radial pulse waveform analyses. Plasma levels of B-type natriuretic peptide (BNP) were measured as an index for cardiac loading. The mean duration of a single hot bath was 12.4 ± 9.9 min. Subject bathing in hot water ≥5 times per week had significantly lower baPWV, central pulse pressure (PP), and BNP after correcting for possible confounding parameters. Stepwise regression analyses revealed that hot water temperature was negatively associated with baPWV, while bathing frequency was negatively related to central PP and BNP. A longitudinal follow-up in 164 subjects showed that hot water bathing ≥5 times per week was associated with significantly lower increase in BNP over time, while the temperature of the water tended to be related to lower increases in carotid max IMT and baPWV. Hot water bathing showed a favorable effect on atherosclerotic and central haemodynamic parameters.

DOI： 10.1038/s41598-018-26908-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM.Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular disease-associated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.

DOI： 10.1536/ihj.17-377

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Clinical implication of a high ankle-brachial index (ABI) is not well known. Based on our previous study, we suspected that body composition may be a determinant of a high ABI and may consequently modulate the clinical significance of a high ABI. Datasets of two studies with independent cohorts, the anti-aging study cohort (n = 1765) and the Nagahama study cohort (n = 8,039), were analyzed in this study, in which appendicular muscle mass was measured by computed tomography and bioelectrical impedance analysis, respectively. Brachial and ankle blood pressures were measured using a cuff-oscillometric method. In the anti-aging study cohort, thigh muscle area (β = 0.387, p < 0.001), but not fat area, showed a strong positive association with the ABI independent of the body mass index (p = 0.662) and other possible covariates, including systolic brachial blood pressure (p = 0.054), carotid hypertrophy (p = 0.559), and arterial stiffness (β = 0.102, p = 0.001). This positive association was replicated in the Nagahama cohort. When the subjects were subdivided by the 75th percentiles of the ABI and appendicular muscle mass, multinomial logistic regression analysis identified insulin resistance as an independent determinant of an elevated ABI in subjects with normal muscle mass (coefficient = 0.134, p = 0.010), whereas insulin resistance was inversely associated with an elevated ABI in subjects with high muscle mass (coefficient = -0.268, p = 0.001). Appendicular muscle mass was a strong determinant of the ABI. The clinical background, particularly insulin resistance, of individuals with an elevated ABI may differ based on the amount of muscle mass.

DOI： 10.1038/s41440-018-0020-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society for Bioscience Biotechnology and Agrochemistry  

We examined whether baPWV could be affected by pork collagen peptide (CP) ingestion. Seventy subjects were randomized into two groups (2.5 g/day CP and 2.5 g/day placebo). A significant reduction in baPWV was observed in the CP group compared to the placebo group. This study demonstrated that pork CP may contribute to the prevention of atherosclerosis in elderly.

DOI： 10.1080/09168451.2018.1434406

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Life Science Publishing Co. Ltd  

Objectives Although vaccination is effective method to prevent influenza infection, current influenza vaccines have inadequate efficacy in general populations. For these reasons a supplement that prevent influenza infection is keenly anticipated. In basic research, it is demonstrated that kuromoji (Lindera umbellate Thunb.) extract has an effectiveness preventing influenza infection. The aim of this study was to assess whether kuromoji extract has a protective effect on influenza infection in clinical settings. Methods In a randomized, double-blind, placebo-controlled, parallel-group study, 135 adult volunteers, they are healthy nursing staff and are met inclusion and exclusion criteria, partici-pated in this study. Sixty-seven participants received test candy (containing 67 mg/day of kuromoji extract), and another 68 participants received placebo candy. Results Test candy significantly reduced influenza infection after 12 weeks compared with placebo candy. Conclusions This is the first clinical study to assess the effectiveness of kuromoji extract in the prevention of influenza infection. Our results suggest that kuromoji extract is a safe supplement for the prevention of influenza infection.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

DOI： 10.1073/pnas.1707151114

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

AIM: It is well known that consumption of isoflavones reduces the risk of cardiovascular disease. However, the effectiveness of isoflavones in preventing dementia is controversial. A number of intervention studies have produced conflicting results. One possible reason is that the ability to produce equol, a metabolite of a soy isoflavone, differs greatly in individuals. In addition to existing data, we sought to confirm whether an apparent beneficial effect in cognitive function is observed after soy consumption in equol producers compared with non-producers. METHODS: The present study was a cross-sectional, observational study of 152 (male/female = 61/91, mean age 69.2 ± 9.2 years) individuals. Participants were divided into two groups according to equol production status, which was determined using urine samples collected after a soy challenge test. Cognitive function was assessed using two computer-based questionnaires (touch panel-type dementia assessment scale [TDAS] and mild cognitive impairment [MCI] screen). RESULTS: Overall, 60 (40%) of 152 participants were equol producers. Both TDAS and prevalence of MCI were significantly higher in the equol producer group than in the non-producer group. In univariate analyses, TDAS significantly correlated with age, serum creatinine, estimated glomerular filtration rate and low-density lipoprotein cholesterol. In multiple regression analysis using TDAS as a dependent variable, equol producer (β = 0.236, P = 0.005) was selected as an independent variable. In addition, multiple logistic regression analysis to assess the presence of MCI showed that being an equol producer was an independent risk factor for MCI (odds ratio 3.961). CONCLUSIONS: Compared with equol non-producers, equol producers showed an apparent beneficial effect in cognitive function after soy intake. Geriatr Gerontol Int 2017; 17: 2103-2108.

DOI： 10.1111/ggi.13029

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Frailty is associated with cognitive impairment and can be used to identify people at high risk for dementia. We developed a simple frailty (SF) score using a combination of low hand grip strength (<32.5 kg in men, <19.5 kg in women), and short one-leg standing time (<20 seconds). These can be easily measured in the clinician's office when seeing patients. We investigated the possible association between SF score and mild cognitive impairment (MCI) in a cross-sectional study with 838 independent middle-aged to elderly participants (319 men, mean age 65.1years). In total, 118 participants were diagnosed with MCI. A SF score of 2 was significantly associated with the presence of MCI (odds ratio 4.6, 95% confidence interval: 1.9-6.9, p = 0.0001) even after adjustment for age and sex. Stepwise regression analyses showed that a SF score of 2 was associated with the presence of MCI, independently of central pulse pressure and silent cerebral infarcts. These findings indicate that the SF score is a useful frailty parameter to predict MCI in an apparently independent population.

DOI： 10.1038/srep46419

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS INC  

Context: We previously reported that single nucleotide polymorphism (SNP)-420 C>G (rs1862513) in the promoter region of RETN was associated with type 2 diabetes. Plasma resistin was tightly correlated with SNP-420 genotypes. SNP-420 is a CpG-SNP affecting the sequence of cytosine-phosphate-guanine dinucleotides. Objective: To examine whether methylation at SNP-420 affects plasma resistin, we analyzed plasma resistin and methylation at RETN SNP-420. Design and Methods: Genomic DNA was extracted from peripheral white blood cells in 2078 Japanese subjects. Quantification of the methylation was performed by pyrosequencing after DNA bisulfite conversion. Results: Methylation at SNP-420 was highest in the C/C genotype (36.9 ± 5.7%), followed by C/G (21.4 ± 3.5%) and G/G (2.9 ± 1.4%; P < 0.001). When assessed in each genotype, methylation at SNP-420 was inversely associated with plasma resistin in the C/C (β = -0.134, P < 0.001) or C/G (β = -0.227, P < 0.001) genotype. In THP-1 human monocytes intrinsically having the C/C genotype, a demethylating reagent, 5-aza-dC, decreased the methylation at SNP-420 and increased RETN messenger RNA. SNP+1263 (rs3745369), located in the 3' untranslated region of RETN, was also associated with methylation at SNP-420. In addition, highly sensitive C-reactive protein was inversely associated with methylation at SNP-420 in the C/C genotype, whereas body mass index was positively associated. Conclusions: Plasma resistin was inversely associated with the extent of methylation at SNP-420 mainly dependent on the SNP-420 genotype. The association can also be explained partially independent of SNP-420 genotypes. SNP-420 could have dual, genetic and epigenetic effects on plasma resistin.

DOI： 10.1210/jc.2016-2417

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3233/JAD-160917

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer's disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.

DOI： 10.3233/JAD-160344

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: Loss of the nocturnal blood pressure (BP) drop is a risk factor for cardiovascular outcomes. However, clinical parameters that predispose to changes in nocturnal BP are currently uncertain. Given the possible involvement of salt sensitivity in nocturnal BP levels, we investigated a hypothesized association between plasma B-type natriuretic peptide (BNP) levels - a marker of body fluid retention - and nocturnal BP in a general population. METHODS: Study participants were 1020 general individuals. Participants were divided into four groups (riser, nondipper, dipper, and extreme dipper) by their percentage changes in nocturnal SBP measured using an ambulatory BP monitor. RESULTS: Plasma BNP levels were positively associated with circadian BP change (β = 0.162, P < 0.001) independently of carotid hypertrophy (β = 0.133, P < 0.001), and awake heart rate (β = -0.102, P = 0.001) and SBP (β = -0.246, P < 0.001). Risers showed 1.6 times higher BNP levels than dippers, whereas oxygen desaturation during sleep was frequently observed in nondippers. Results of multinomial logistic regression analysis indicated that BNP level was a significant determinant for the riser pattern [odds ratio (OR) 1.27 (BNP 10 pg/ml), P < 0.001], whereas oxygen desaturation was specifically associated with the nondipping pattern (OR 1.04, P = 0.001). When participants were subdivided by BNP level, risers were more frequent in the high BNP subgroup (19.5%) than in the low BNP subgroup (6.7%) (OR 3.39, P < 0.001). CONCLUSION: A slight increase in plasma BNP level was independently associated with rising nocturnal BP. Our results may help to understand the pathophysiology of circadian BP variation, and be a clue to identify individuals who require careful BP monitoring.

DOI： 10.1097/HJH.0000000000001104

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP -358 G>A, followed by rs1423096 C>T, SNP -420 C>G, and rs10401670 C>T (P = 5.39×10-47, 1.81×10-22, 2.09×10-16, and 9.25×10-15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.

DOI： 10.1152/physiolgenomics.00040.2016

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Masked hypertension (HT) is a known risk factor for cardiovascular outcomes. Postural blood pressure (BP) dysregulation is another BP phenomenon representing cardiovascular frailty. Given their several shared risk factors, we suspected an inter-relationship between these two BP phenomena. Here we investigated a possible relationship between masked HT and postural BP dysregulation in a general population. Study subjects were 884 apparently healthy individuals (aged 66.3±8.9 years). Masked HT was assessed on the basis of the ambulatory monitored average awake BP and office-measured BP values. Orthostatic BP change was measured at our office after a subject was asked to actively stand up. A strong inverse relationship was noted for orthostatic systolic BP (SBP) change and office-to-awake SBP differences (office-awake BP) (r=-0.422, P<0.001), and these relationships were replicated in the second-visit measurements (n=101, r=-0.326, P=0.001). Multivariate analysis revealed that the inverse association was independent (β=-0.23, P<0.001) of possible covariates, including baseline office BP and antihypertensive treatment. Orthostatic HT (OHT), which is defined as postural increases in SBP >10 mm Hg, 3 min after standing (P=0.001), but not transient HT at only 1 min (P=0.767), was associated with greater office-to-awake SBP differences than in orthostatic normotensive subjects. Among apparently normotensive subjects, the frequency of masked HT was therefore significantly greater in subjects who showed OHT 3 min after standing (52.1%) compared with controls (27.5%) (odds ratio=3.01, P=0.001). We observed an intra-individual relationship between the postural BP change and the office-to-awake BP differences, and subjects who showed OHT were likely to have masked HT irrespective of antihypertensive treatment.

DOI： 10.1038/hr.2016.43

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Early detection of pathological changes in the vasculature is required to identify individuals at risk of cardiovascular diseases. Noninvasive measurement of the second derivative of photoplethysmogram (SDPTG) might aid in evaluating vascular aging. Here we clarified the diagnostic significance of four SDPTG indices for end-organ damage. A total of 1613 community residents (65±10 years) were enrolled. Changes in blood flow volume at the forefinger were measured by photoplethysmography. SDPTG was computationally calculated from the plethysmogram, and the height of five peaks (a-e) on the SDPTG was measured. Carotid intima-media thickness (IMT), brachial-to-ankle pulse wave velocity (baPWV) and silent cerebral lesions were used as indices of end-organ damage. Multivariate analysis identified age, sex, systolic blood pressure and heart rate as strong determinants for the evaluated SDPTG indices, namely b/a, d/a and aging index ([b-d-c-e]/a). In addition, poor glycemic control and carotid IMT were also weakly associated with the SDPTG indices. Compared with other established risk factors, however, the association between the SDPTG indices and carotid IMT was weak or insignificant (b/a: β=0.069, P=0.002; d/a: β=-0.009, P=0.669; and aging index: β=0.047, P=0.037). Further, no significant association was noted between the SDPTG indices and silent lacunar infarction (b/a: P=0.111; d/a: P=0.263; and aging index: P=0.167) and periventricular hyperintensity (b/a: P=0.587; d/a: P=0.254; and aging index: P=0.429). Although the SDPTG indices evaluated here might represent structural and functional changes in arteries, they exhibited limited diagnostic significance for pathophysiological changes in large arteries, as well as small vessel diseases of the brain.

DOI： 10.1038/hr.2016.18

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.

DOI： 10.3233/JAD-150939

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

OBJECTIVE: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. METHODS: To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. RESULTS: We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aβ)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound-B positron emission tomography imaging. INTERPRETATION: Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.

DOI： 10.1002/ana.24612

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1523/JNEUROSCI.3757-15.2016

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

Central pontine myelinolysis (CPM), which was originally considered to be the result of rapid correction of chronic hyponatremia, is not necessarily accompanied by hyponatremia or drastic changes in serum sodium level. Here, we report a case of an anorexic 55-year-old male with a history of pharyngo-laryngo-esophagogastrectomy, initially hospitalized with status epilepticus. Although his consciousness gradually recovered as we were controlling his convulsion, it deteriorated again with new onset of anisocoria, and magnetic resonance imaging (MRI) at this point revealed CPM. Rapid change of serum sodium or osmolarity, which is often associated with CPM, had not been apparent throughout his hospitalization. Instead, a review of the serum biochemistry test results showed that serum phosphate had drastically declined the day before the MRI first detected CPM. In this case, we suspect that hypophosphatemia induced by refeeding syndrome greatly contributed to the occurrence of CPM.

DOI： 10.1159/000440711

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley-Blackwell  

Objective Pro-inflammatory cytokines can exacerbate muscle fiber damage in dystrophinopathy. The aim of the present study was to identify cytokine/chemokine alterations in the muscle tissues of mdx mice, a model of dystrophinopathy, and the beneficial effects of anti-proinflammatory cytokine therapy. Methods A total of 23 cytokines and chemokines were quantitatively measured in muscle tissues from mdx mice by fluorescent bead-based immunoassay. The mdx mice were treated with anti-tumor necrosis factor-α (TNF-α) and anti-interleukin-6 (IL-6) drugs, and their physical condition was evaluated by Rotarod and muscle damage by histopathological analysis. Results Levels of TNF-α and IL-6 were elevated at 14 days (P14), before a transient increase of macrophage and neutrophil-activating pro-inflammatory cytokines/chemokines, such as C-C motif ligand 2 (CCL2), CCL4 and KC (mouse C-X-C motif ligand 8 homolog), at P20. Administration of an anti-TNF-α drug (etanercept) and an anti-IL-6 receptor antibody (MR16-1) from P7 improved physical performance, and reduced both the area of basophilic fibers that indicated degenerating/regenerating fibers and CD68-positive macrophage infiltration. Initiating therapy at P7 inhibited the elevation of CCL2, CCL4 and KC more effectively than at P13. Conclusions The early administration of anti-TNF-α and anti-IL-6 drugs attenuated muscle fiber degeneration in a mouse model of dystrophinopathy.

DOI： 10.1111/cen3.12111

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We herein report a 32-year-old woman with adult-onset reducing body myopathy (RBM) who had a mutation in the four-and-a-half LIM domain 1 gene (FHL1) and showed a marked asymmetrical involvement of sternocleidomastoid and trapezius muscles. At 30 years of age she noticed bilateral foot drop, and over the next two years developed difficulty raising her right arm. At 32 years of age she was admitted to our hospital for a diagnostic evaluation. Neurological examination showed moderate weakness and atrophy of her right sternocleidomastoid muscle, right trapezius muscle, and bilateral upper proximal muscles. There were severe weakness and atrophy of her bilateral tibialis anterior muscles. Her deep tendon reflexes were hypoactive in her upper extremities. Her serum creatine kinase level was mildly increased. Muscle biopsy specimens from the left tibialis anterior muscle revealed marked variation in fiber size, some necrotic or regenerating fibers, and reducing bodies. Gene analysis of FHL1 demonstrated a mutation: a heterozygous missense mutation of c.377G>A (p. C126T) in FHL1. Compared with previous adult-onset RBM cases harboring mutations in FHL1, our case was characterized by asymmetrical atrophy of the sternocleidomastoid and trapezius muscles.

DOI： 10.1016/j.jns.2014.05.056

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS LTD  

We report the first case of definite neuromyelitis optica (NMO) with a pathogenic mitochondrial DNA (mtDNA) mutation for Leber's hereditary optic neuropathy (LHON) (G11778A point mutation). A 36-year-old Japanese woman had experienced recurrent neurological symptoms originating from involvements of the optic nerves and spinal cord. She finally lost her bilateral vision, and spastic paraparesis and sensory disturbances below the T6 level remained despite intensive immunotherapies. Brain and spinal magnetic resonance imaging (MRI) revealed T2-high-intensity lesions in the optic nerves and thoracic spinal cord, but no lesions in the brain. A blood examination revealed positivity for both anti-aquaproin-4 antibodies and an LHON mtDNA mutation.

DOI： 10.1177/1352458513513057

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

To understand the status of postgraduate education in neurology in Japan, the Committee for the Education of Undergraduate Students and Junior Residents within the Japanese Society of Neurology investigated the four-year trend at 80 medical schools from 2009 to 2012. The mean number of new students to each postgraduate school increased from 1.24 to 1.67 during these four years. After training clinical neurology, more than half of the neurological residents entered the postgraduate schools. Students in the postgraduate schools seemed to be researching major neurological diseases using various methods at each neurology laboratory. However, some problems were suggested. First, the mean number of newcomers to the neurology departments of the universities decreased gradually from 2.29/year to 1.96/year. Second, many of the postgraduate students were working in patient services at university hospitals or as part-time workers at other hospitals, and may not have sufficient time for their research projects. Third, many of the postgraduate students were carrying out research at each affiliated department of neurology, and may not have the opportunity to work in laboratories specializing in basic science. Finally, there may not be sufficient opportunities for further research at other laboratories in Japan or overseas after they finished their work at postgraduate school.

DOI： 10.5692/clinicalneurol.54.349

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.

DOI： 10.1016/j.jns.2013.06.027

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bpa.12040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a sporadic case of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) confirmed by biopsy and colony-stimulating factor 1 receptor (CSF1R) sequencing. A 28-year-old woman developed progressive spastic gait and dysarthria. Brain T2/FLAIR-weighted magnetic resonance imaging showed bilateral high signal intensity lesions in the parietal deep white matter, which subsequently extended anteriorly. Biopsied brain specimens demonstrated demyelinated white matter tissue with axonal spheroids infiltrated with foamy macrophages, and CD8(+) and CD4(+) T cells. She had a heterozygous mutation, c.2381T>C (p.782 Ile>Thr), in CSF1R. This is the first genetically proven case of HDLS mimicking primary progressive multiple sclerosis.

DOI： 10.1177/1352458513489854

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Previous rat studies have utilized freeze lesioning of neonatal animals to model FCD; however, such models are unable to demonstrate spontaneous seizures without seizure-provoking events. Therefore, we created an animal model with multiple FCD, produced during embryonic development, and observed whether spontaneous seizures occurred. Furthermore, we examined the relationship between FCD and epileptogenesis using immunohistochemistry. At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Electroencephalogram (EEG) and video recording were performed from postnatal day (P) 35 to P77. Brain tissues were examined immunohistochemically at P28 and P78 using semiquantitative densitometry. Eleven of 16 rats (68.8%) showed spontaneous seizures arising in the hippocampus from P47. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal EEG discharges. FCD was observed in the bilateral frontoparietal lobes. The expression levels of N-methyl-d-aspartate receptor (NMDAR) subunits 1, 2A, 2B, the glutamate/aspartate transporter and the glial glutamate transporter 1 (GLT1) at FCD sites were increased at P28 and P78. There were no major histological abnormalities in the hippocampi compared with those in the cortex. However, the expression levels of NMDAR 2A and 2B were increased at P28. Levels of NMDAR1, 2A and 2B, the glutamate/aspartate transporter and GLT1 were also increased at P78. We created an animal model showing spontaneous seizures without a provoking event except for the existence of cortical dysplasia, and without a genetic or general systematic cause like MAM injection or irradiation. The seizures resembled human temporal lobe epilepsy both clinically and on EEG. Alterations in the levels of glutamatergic and GABAergic receptors were investigated during growth. This model should enable better clarification of the mechanisms underlying the development of human epilepsy.

DOI： 10.1016/j.eplepsyres.2013.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.53.695

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

We report a 58-year-old man showing spastic paraparesis due to medulla oblongata compression by tortuous vertebral arteries. He noticed weakness of both legs and gait disturbance at the age of 58 years and his symptoms progressively worsened during the following several months. General physical findings were normal. Blood pressure was normal and there were no signs of arteriosclerosis. Neurological examination on admission revealed lower-limb-dominant spasticity in all four extremities, lower-limb weakness, hyperreflexia in all extremities with positive Wartenberg's, Babinski's and Chaddock's signs, mild hypesthesia and hypopallesthesia in both lower limbs, and spastic gait. Cranial nerves were all normal. Serum was negative for antibodies against human T-cell lymphotropic virus-1 antibody. Nerve conduction and needle electromyographic studies of all four limbs revealed normal findings. Cervical, thoracic and lumbo-sacral magnetic resonance imaging (MRI) findings were all normal. Brain MRI and magnetic resonance angiography demonstrated bilateral tortuous vertebral arteries compressing the medulla oblongata. Neurovascular decompression of the right vertebral artery was performed because compression of the right side was more severe than that of the left side. Post-operative MRI revealed outward translocation of the right vertebral artery and relieved compression of the medulla oblongata on the right side. The patient's symptoms and neurological findings improved gradually after the operation. Bilateral pyramidal tract signs without cranial nerve dysfunction due to compression of the medulla oblongata by tortuous vertebral arteries are extremely rare and clinically indistinguishable from hereditary spastic paraplegia (HSP). Although we did not perform a genetic test for HSP, we consider that the spastic paraparesis and mild lower-limb hypesthesia were caused by compression of the medulla oblongata by bilateral tortuous vertebral arteries based on the post-operative improvement in symptoms. Given the favorable effects of surgery, tortuous vertebral arteries should be considered in the differential diagnosis of patients presenting with progressive spastic paraparesis.

DOI： 10.5692/clinicalneurol.53.356

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report the case of a 62-year-old man with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO). He developed gait disturbance at 54 years of age, muscle weakness at 56 years, and difficulty hearing at 58 years. His brother had muscle weakness in both legs from age 20 years, and was diagnosed with Charcot-Marie-Tooth disease because he had muscle weakness of the four extremities, decreased CMAP and SNAP amplitudes on peripheral nerve conduction tests, and loss of large myelinated fibers and onion-bulb formations on sural nerve biopsy. His brother died aged 46 years, but no accurate cause of death was identified. Neurological examination of the present patient revealed bilateral ptosis, external ophthalmoparesis, dysarthria, dysphagia, sensorineural hearing loss, mild weakness and atrophy of proximal muscles in all four limbs, severe sensory ataxia, and disturbance of deep sensation in his legs. He showed elevation of lactate and pyruvate levels in cerebrospinal fluid and serum. An aerobic exercise test disclosed a marked increase in lactate and pyruvate levels in serum. On nerve conduction study, amplitudes of CMAP and SNAP, and F wave-evoked frequency were decreased. Needle electromyography showed chronic neurogenic patterns with fibrillation potentials in the extremity muscles. Head MRI demonstrated T2 prolonged lesions in the bilateral basal ganglia, while brain MRS revealed a small lactate peak. Biopsy of his left lateral vastus muscle showed ragged-red fibers and group atrophy, and some muscle fibers had decreased cytochrome c activity. Left sural nerve biopsy revealed a marked loss of large myelinated fibers, and some onion-bulb formations. Genetic testing disclosed a large mtDNA deletion in the biopsied muscle. Among nuclear genes, we found point mutations in ANT-1 (exon 1 c.105G>A, 5' untranslated region) and POLG-1 (exon 4, c.1218G>A, p. and exon 23 c.3920C>T, p.A1217V). We diagnosed SANDO. This is the first case of SANDO with large mitochondrial DNA deletions in Japanese.

DOI： 10.5692/clinicalneurol.53.205

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記述言語：英語   出版者・発行元：B M J PUBLISHING GROUP  

DOI： 10.1136/jnnp-2012-302281

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

INTRODUCTION: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. METHODS: A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. RESULTS: A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. CONCLUSIONS: Progressive myopathy involvement could be a hitherto unknown manifestation of APECED.

DOI： 10.1002/mus.23321

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which microglia and T cells play significant roles in disease progression. However, it remains unknown whether these cells are toxic or protective. The present study aimed to clarify the developmental age-related alterations of neuronal, glial and T cell responses to acute neuron injury in non-transgenic (N-Tg) mice, and the in vivo effects of mSOD1 on these changes by studying N-Tg and mSOD1-Tg mice subjected to unilateral hypoglossal nerve axotomy at young (8 weeks) and adult (17 weeks) ages. Adult N-Tg mice showed increased neuronal viability on day 21 after axotomy and trends toward increased numbers of recruited microglia on day 3 and T cells on day 7, in the hypoglossal nucleus, compared with young N-Tg mice. Quantitative comparisons between mSOD1-Tg and N-Tg mice at the same ages, on day 3 after axotomy, showed that microglial recruitment was significantly lower in mSOD1-Tg mice than in 17-week-old N-Tg mice (the disease progression stage), but the same difference was not seen in 8-week-old mice (the presymptomatic stage), despite good preservation of hypoglossal neurons. Infiltration of CD3-positive T cells, mostly CD4-positive, on day 7 and the viability rate of hypoglossal neurons on the operated side compared with the contralateral side on day 21 were significantly decreased in mSOD1-Tg mice compared with N-Tg mice aged 17 weeks, but the same difference was not seen in mice aged 8 weeks. On day 3 after axotomy, expression levels of IGF-1 mRNA in the operated hypoglossal nucleus were significantly lower in mSOD1-Tg mice than N-Tg mice at 17 weeks of age. The observation that depressed microglial and T cell responses and expression of neurotrophic factors coincided with reduced neuronal viability in adult mSOD1-Tg mice suggests that diminished neuroprotective functions of mSOD1 microglia and T cells may contribute to exaggerated neuronal death.

DOI： 10.1016/j.expneurol.2012.01.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The purpose of this study was to determine the optimal computational options in voxel-based morphometry (VBM) for discrimination between Alzheimer's disease (AD) patients and healthy control (HC) subjects. MATERIALS AND METHODS: Structural magnetic resonance images of 24 AD patients and 26 HC subjects were analyzed using VBM to determine brain regions with significant gray matter (GM) loss due to AD. The VBM analyses were performed with 4 different computational options: gray matter concentration (GMC) analysis with and without global normalization, and gray matter volume (GMV) analysis, with and without global normalization. Statistical maps calculated with the 4 computational options were obtained at 3 different P-value thresholds (P < 0.001, P < 0.0005, and P < 0.0001, uncorrected for multiple comparisons), yielding a total of 12 sets of maps, from which regions-of-interest (ROI) were generated for subsequent analyses of performance in terms of discrimination between AD patients and HC subjects as based on the mean value of either the GMC or GMV within the ROI for each of the 12 maps. Discrimination performance was evaluated by means of comparing the area-under-the-curve derived from the receiver-operating characteristic analysis as well as on the accuracy of the discrimination. RESULTS: Discrimination based on GMC analysis resulted in better performance than that based on GMV analysis. The best discrimination performance was achieved with GMC analysis either with or without proportional global normalization. CONCLUSION: The findings suggested that GMC-based VBM is better suited than GMV-based VBM for discrimination between AD patients and HC subjects.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a case of a small cortical infarction in the postcentral gyrus that presented an isolated hemicape-like sensory disturbance. A 47-year-old man suddenly developed numbness and paresthesia in the left neck, shoulder, arm, and upper trunk. Examination revealed hypoesthesia to touch and pain in these areas along with a hemicape-like distribution. The sensitivity to cold and vibration was normal, and two-point discrimination and graphesthesia were preserved. The patient had a normal visual field, muscle strength, and reflexes, and there were no neuropsychological deficits. Magnetic resonance imaging (MRI) demonstrated a fresh, small cerebral infarction in the right postcentral gyrus, which was superior medial to the precentral knob. The area of infarction in this patient corresponds well with the area of the upper trunk, neck, head, shoulder, and arm in the sensory homunculus drawn by Penfield and Rassumussen. The spinal MRI was normal. Transesophageal echocardiography disclosed a patent foramen ovale with a right-to-left-shunt. The patient was diagnosed as having acute cerebral infarction, probably due to paradoxical embolism, and was treated with warfarin. A small localized infarct in the postcentral gyrus can present an isolated sensory disturbance with an atypical hemicape-like distribution.

DOI： 10.5692/clinicalneurol.52.178

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.52.227

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Hereditary hemorrhagic telangiectasia (HHT) is characterized by systemic vascular diseases mainly shown as arterio-visnous fistula (AVF). Here, we presented a 29-year-old woman with HHT complicated with migraine with aura (MWA) and vertigo. At the age of twelve years, she developed migraine with visual aura. At that time, migraine attacks were seen three times a year. At the age of 29 years, she also developed speech disturbance as migraine aura. At the ages of 20 and 29 years, she repeatedly suffered from positional vertigo attacks for a month. Physical examination revealed dilation of the capillary vessels at tongue, soft palate, and nasal mucosa and AVFs were located in the upper cervical cord, parietal lobe, and bilateral lungs. These clinical findings were consistent with the diagnostic criteria of HHT. Embolization of pulmonary AVF decreased the frequency of migraine attacks during 2-year follow-up after the embolization. The frequency of migraine in patients with HHT is higher than that of general population as well as the prevalence of vertigo. Therefore, MWA and vertigo presented in the patient with HHT suggests that there is a common pathological mechanism of dysfunction of endothelial cells and R-L shunt, among HHT, MWA, and vertigo.

DOI： 10.5692/clinicalneurol.52.499

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DOI： 10.1109/ICCME.2012.6275685

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その他リンク： http://orcid.org/0000-0002-3449-3988

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Alzheimer's disease (AD) patients have visuospatial deficits due to parietal dorsal stream dysfunction. Two distinct dorsal flows have been proposed: the inferior parietal (ventro-dorsal (v-d)) and superior parietal (dorso-dorsal (d-d)) streams. We aimed to elucidate how the two dorsal streams are altered in patients with amnestic mild cognitive impairment (aMCI) and AD. Thus, the psychophysical threshold measurements and visual event-related potentials (ERPs) were recorded in patients with aMCI and AD, and in healthy old and young adults. The visual stimuli included radial optic flow (OF) derived from the v-d stream and horizontal (HO) motion conveyed from the d-d stream. The motion thresholds between aMCI patients and old adults were comparable. However, AD patients showed significantly higher motion thresholds for both stimuli compared with other groups. In lower-level ERPs, there were no significant differences in P1 (100 ms) and N1 (130 ms) for both stimuli among the groups. For higher-level ERPs, aMCI patients showed the prolonged latency of OF-specific P200 (v-d origin) and comparable latency of motion-related N170 (V5/MT origin) for both stimuli compared with old adults. In AD patients, both N170 and P200 latencies were significantly prolonged compared with other groups. P200 latency was closely correlated with the Mini-Mental State Examination score. These findings indicate that the v-d function related to OF perception is selectively impaired in aMCI, whereas AD has impairment of the distributed higher-level dorsal stream. Therefore, OF-specific P200 can be useful for detecting early functional changes of the brain in aMCI.

DOI： 10.3233/JAD-2011-110167

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

RATIONALE AND OBJECTIVES: The relative roles of arterial spin-labeling (ASL) perfusion imaging and magnetic resonance morphological assessment in diagnosing Alzheimer's disease (AD) have not been established. Our purposes were to directly compare the diagnostic performance of ASL regional cerebral blood flow (rCBF) measurement and that of morphological assessment, and to determine whether or not the combination of the two methods improves diagnostic performance. MATERIALS AND METHODS: We analyzed 23 consecutive, retrospectively identified AD patients and 23 healthy control subjects. For each subject, both high-resolution T1-weighted images and ASL perfusion images were obtained. A linear discriminant analysis was performed to distinguish the AD patients from the control subjects based on the three imaging parameters: 1) globally normalized gray matter (GM) density determined by voxel-based morphometry (VBM) procedures, 2) normalized rCBF calculated from ASL data, and 3) the combination of the two. The discriminative abilities of these methods were evaluated by the area under the curve (AUC) derived from receiver-operating characteristics analysis. RESULTS: The morphological assessment based on the globally normalized GM density resulted in an AUC of 0.779, whereas ASL-normalized rCBF analysis achieved better performance (AUC = 0.893). The combination of the two methods performed better (AUC = 0.919) than either method alone. CONCLUSION: Normalized rCBF measurement by ASL may perform better than morphological analysis based on the VBM procedure in discriminating AD patients from healthy control subjects. The combination of the two approaches was more effective than either method alone.

DOI： 10.1016/j.acra.2011.07.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

We report a 29-year-old man who presented with a 2-year history of progressive stiffness and painful spasms limited to the bilateral lower limbs, exaggerated by auditory and tactile stimuli. His deep tendon reflexes were slightly increased in both lower extremities. His plantar response was flexor. His serum and cerebrospinal fluid were negative for anti-glutamic acid decarboxylase antibodies. Electromyography of antagonist muscle pairs in his distal lower limbs revealed a failure of reciprocal inhibition. We used transcranial magnetic stimulation with a paired-pulse paradigm, delivered to the cortical area of the upper and lower limbs, and revealed significantly enhanced facilitation only in the area of his lower limbs, but not that representing his upper limbs. His symptoms were improved substantially by 20mg/day of oral diazepam. To our knowledge this is the first report of a patient with hyperexcitability limited to the lower limb motor system in a patient with stiff-leg syndrome.

DOI： 10.1016/j.jocn.2011.03.021

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5692/clinicalneurol.51.884

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a 68-year-old man who exhibited mild dysarthria and mild right hemiparesis resulted from hypoperfusion of the left hemisphere. An MR angiography showed a severe stenosis at the second portion of left middle cerebral artery (MCA). After the beginning of treatment, the patient suffered from hoarseness, followed by breathing failure. The laryngeal fiber exhibited right vocal cord paresis. Unilateral cortico-bulbar tract dysfunction does not typically cause vocal cord palsy. However, several cases indicate the involvement of a dominant projection from the contralateral cortico-bulbar tract to the vocal cord. In the present case, hypoperfusion of the left hemisphere might have temporarily produced right vocal cord palsy, considering the stenosis of the left MCA.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Charles Bonnet syndrome refers to visual hallucinations in patients with visual acuity loss or visual field loss without dementia. We report a case of Charles Bonnet syndrome following syphilitic optic neuritis. A 62-year-old man was admitted to our hospital suffering acute bilateral visual loss in a few months. On admission, he was almost blind and his optic discs were found to be atrophic on fundoscopy. In addition to increased cell counts and protein concentration in cerebrospinal fluid (CSF), serum and CSF rapid plasma reagin tests were positive. A diagnosis of syphilitic optic neuritis was made and he was treated with intravenous penicillin G (24 million units per day for 14 days) without any recovery. After treatment finished, he began to experience complex, vivid, elaborate and colored visual hallucinations. He recognized these visions as unreal and felt distressed by them. No cognitive impairment was observed on several neuropsychological tests. We diagnosed the patient as suffering from Charles Bonnet syndrome. Brain MRI revealed diffuse mild atrophy of the cerebral cortex and multiple T2 high signal intensity lesions in the deep cerebral white matter. Single photon emission computed tomography revealed decreased regional cerebral blood flow in bilateral medial occipital lobes. Administration of olanzapine resulted in a partial remission of visual hallucinations. Charles Bonnet syndrome following syphilitic optic neuritis is rare. In the present case, visual loss and dysfunction of bilateral medial occipital lobes may have triggered the visual hallucinations, which were alleviated by olanzapine.

DOI： 10.5692/clinicalneurol.51.595

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS LTD  

This report describes, for the first time, an occurrence of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a 19-year-old female with neuromyelitis optica (NMO) spectrum disorder, who had anti-aquaporin-4 (AQP4) antibody. A high signal intensity lesion on T2-weighted MRI was detected in the midbrain tegmentum adjacent to the aqueduct, and presumably involved the medial longitudinal fasciculus bilaterally at the caudal levels. Plasma exchange resolved both WEBINO syndrome and the midbrain lesion. Although WEBINO syndrome is occasionally reported in multiple sclerosis patients, diagnosis of NMO should not be excluded in patients with WEBINO syndrome, because AQP4 is expressed abundantly around the periaqueductal region.

DOI： 10.1177/1352458510391690

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 61-year-old man with slowly progressive gait disturbance and paresthesia in the lower extremities following a total gastrectomy for gastric cancer 23 years previously. The patient presented with hyperreflexia, peripheral sensory neuropathy, and cerebellar ataxia. Magnetic resonance imaging showed atrophy of the cerebellum, and electrophysiological findings suggested the presence of disorder in both sides of the pyramidal tract, dorsal column, peripheral nerves, and optic nerve. Laboratory findings revealed anemia, neutropenia, and a remarkably low serum copper level (10 microg/dl; normal: 68-128). His serum vitamin E was slightly low and his serum vitamin B12 was within the normal limits. After administering an oral copper supplement, his symptoms improved with normalization of the serum copper level. We need to pay attention to myeloneuropathy caused by copper deficiency if the patient has a past history of total gastrectomy.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a case of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) concomitant with acquired von Willebrand syndrome. A 33-year-old man developed motor and sensory polyneuropathy with electrophysiological conduction slowing. At this time, M-protein was absent He was diagnosed with CIDP and received intravenous immunoglobulin and subsequent oral corticosteroids, which resulted in almost complete remission for over 10 years. At the age of 44, he presented with chronic anemia. Laboratory tests and colonoscopy revealed that he had acquired von Willebrand syndrome with monoclonal gammopathy of undetermined significance (IgG lambda type) and colon cancer. Bleeding symptoms were.resolved with intravenous immunoglobulin, but not with supplementation of factor VIII. Shortly after successful excision of the cancer, CIDP and acquired von Willebrand syndrome simultaneously recurred. Intravenous immunoglobulin produced rapid improvement of both neurological and hematological abnormalities. Concurring CIDP and acquired von Willebrand syndrome in the present case may indicate that the conditions have a partly common immunological background including monoclonal gammopathy and a potential common autoantibody-mediated mechanism. Alternatively, dysfunction of von Willebrand factor may increase blood-nerve barrier permeability, inducing the recurrence of CIDP.

DOI： 10.5692/clinicalneurol.51.334

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ana.22319

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

OBJECTIVE: To determine which brain regions are relevant to deterioration in abstract reasoning as measured by Raven's Colored Progressive Matrices (CPM) in the context of dementia. METHODS: MR images of 37 consecutive patients including 19 with Alzheimer's disease (AD) and 18 with amnestic mild cognitive impairment (aMCI) were retrospectively analyzed. All patients were administered the CPM. Regional grey matter (GM) volume was evaluated according to the regimens of voxel-based morphometry, during which a non-linear registration algorithm called Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra was employed. Multiple regression analyses were used to map the regions where GM volumes were correlated with CPM scores. RESULTS: The strongest correlation with CPM scores was seen in the left middle frontal gyrus while a region with the largest volume was identified in the left superior temporal gyrus. Significant correlations were seen in 14 additional regions in the bilateral cerebral hemispheres and right cerebellum. CONCLUSION: Deterioration of abstract reasoning ability in AD and aMCI measured by CPM is related to GM loss in multiple regions, which is in close agreement with the results of previous activation studies.

DOI： 10.1007/s00330-010-1939-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 25-year-old woman complained of numbness of the extremities, following muscle rigidity and tenderness. The presence of anti-voltage-gated potassium channel antibody led to the diagnosis of Isaacs' syndrome. Twenty-seven months after the first symptom, she developed a pricking pain sensation in the lateral left foot, and then gradually developed a purple skin lesion resembling frostbite. The lesion completely disappeared 2 days later. An incidental episode occurred at the same site 8 months later. Frostbite-like skin lesions may be a rare autonomic manifestation in Isaacs' syndrome.

DOI： 10.2169/internalmedicine.50.4998

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.

DOI： 10.3233/JAD-2011-110140

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000332033

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We studied the effects of G-CSF on microglial reactions in mutant SOD1 (mSOD1)-Tg (G93A) ALS model mice. Following hypoglossal axotomy, the numbers of neurons and microglia expressing GDNF were significantly lower in mSOD1-Tg mice than in non-transgenic (NTG) littermates. This decrease in the number of neurons after axotomy and a decrease in the number of large myelinated axons in mSOD1-Tg mice over the disease course were improved by G-CSF, which also increased microglial recruitment. Impaired migration of cultured mSOD1-Tg microglia to MCP-1 was recovered following G-CSF treatment. Restoration of microglial responses by G-CSF may contribute to its neuroprotective effects.

DOI： 10.1016/j.jneuroim.2010.07.002

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DOI： 10.1016/j.jns.2010.05.014

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

We report a case of mononeuropathy multiplex with idiopathic thrombocytopenic purpura (ITP). A 78-year-old man developed patches of purpura on his left forearm. His platelet count was 11,000/microl and platelet-associated IgG was elevated. He was diagnosed as having ITP. At the beginning of the following month, he noticed dysesthesia and weakness of his left finger and left lower limb, as well as dysesthesia of his bilateral lower thighs. Neurological examination revealed weakness in the area of the left ulnar nerve and of the left anterior tibial muscle. Dysesthesia presented in the area of the left ulnar nerve and bilateral superficial peroneal nerves. Nerve conduction studies revealed asymmetric axonal sensorimotor neuropathy (mononeuropathy multiplex). A cerebrospinal fluid specimen showed a normal cell count and normal protein level Serum anti-ganglioside antibody was negative. The platelet count gradually increased after the introduction of corticosteroid therapy. His neurological deficits and electrophysiological findings also improved. Immune-mediated neuropathy was suggested as the cause of his mononeuropathy multiplex with ITP.

DOI： 10.5692/clinicalneurol.50.482

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 31-year-old woman with Crohn's disease that had been refractory to drug therapies for 7 years had been treated with infliximab for a year. She was admitted to our hospital because of truncal ataxia and bulbar palsy, which presented following aseptic meningitis. Neurological examination revealed abducens paresis on the left, gaze-evoked nystagmus on upward and rightward gaze, right facial muscle weakness, bulbar palsy, weakness in the right upper extremity, limb ataxia predominantly on the left side, diminished sense in the lower extremities predominantly on the right, diffuse hyperreflexia in all extremities. Antibodies to Epstein-Barr virus (EBV) in serum demonstrated a previous infection pattern, and EBV-DNA was detected in peripheral blood and cerebrospinal fluid (CSF) by PCR. CSF analysis indicated pleocytosis, an elevation of IgG index and a marked increase in the level of myelin basic protein. FLAIR MRI images revealed multiple hyperintense lesions in the brainstem, subcortical white matter, and cervical spinal cord. Accordingly, we diagnosed her as having acute disseminated encephalomyelitis (ADEM), associated with reactivated EBV infection. Although gancyclovir, plasma exchange and intravenous high dose immunoglobulins were not effective, repetitive use of methylprednisolone pulse therapy alleviated her symptoms and the abnormal MRI lesions. It is suggested that the reactivated EBV infection caused by infliximab may have contributed to the development of ADEM in this case. Besides the demyelinating event directly induced by anti-TNF-alpha therapy, we should pay attention to the occurrence of reactivated EBV-triggered ADEM during anti-TNF-alpha therapy.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

We report a case of paraneoplastic neurological syndrome with anti-neuronal antibodies, namely anti-Hu and anti-GluR epsilon 2 antibodies in sera. A 72-year-old male had a transient history of eye movement disorder and sensory neuropathy, which improved spontaneously. Two years later, he was admitted to another hospital because of gait disturbance, numbness of the hands and an attack of unconsciousness with generalized convulsion. He was admitted to our hospital with prolonged consciousness disturbance and muscular weakness of all extremities. On admission his consciousness deteriorated slightly without neck stiffness. His cranial nervous system was normal except for incomplete abduction and elevation of both eyes. The patient had severe distal dominant weakness and atrophy in the muscles of all four limbs. Muscle tonus was decreased and hyporeflexia was noted in the four extremities. Plantar response was extensor. Neither sensory disturbance nor ataxia was observed. Cranial MRI showed T2-weighted high intensity lesions in the bilateral mesial temporal lobes, including the hippocampi. A nerve conduction study revealed motor-dominant peripheral neuropathy with prolonged latency; the amplitudes of compound muscle action potentials were severely reduced in all four limbs and those of sensory nerve action potentials were moderately reduced in the right upper and lower extremities. We also found a left hilar lymphadenopathy showing accumulation of FDG on PET, suggesting a possibility of malignancy. Anti-Hu and anti-GluR epsilon 2 antibodies were detected in sera but not in CSF. We diagnosed him with limbic encephalitis and peripheral neuropathy due to paraneoplastic neurological syndrome and treated him with two courses of intravenous immunoglobulin (IVIg) (400 mg/kg, 5 days). The consciousness disturbance, and prolonged distal latency revealed by motor nerve conduction studies improved slightly. Although the roles of anti-neuronal antibodies in paraneoplastic conditions remain unknown, we consider that IVIg may be worth using to treat cases with anti-Hu and anti-GluR epsilon 2 antibodies.

DOI： 10.5692/clinicalneurol.50.467

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 39-year-old woman suddenly developed numbness of the left arm following mild weakness of the left upper and lower extremities, blindness in the left visual field, and difficulty finding words. Her symptoms lasted for two hours with no deficit remaining. Six months after the first episode, the first of several more occurred. Two of the episodes were followed by nausea and a non-pulsative headache around the left temporo-parietal regions and the orbit. She had also been suffering recurrent skin eruptions for the previous two years. There was no family history of migraine. Her neurological symptoms fulfilled the criteria of sporadic hemiplegic migraine (SHM). Biopsy of skin eruption revealed lymphocytic infiltration and liquefied degeneration of basal lamina. These findings were compatible with systemic lupus erythematosus (SLE). There were no lesions evident on brain MR. We diagnosed SLE and after administration of aspirin (100 mg/day) and lomerizine hydrochloride (10 mg/day), her neurological symptom completely disappeared. SHM-like headache in patients with SLE is extremely rare. Although an autoimmune or thrombotic mechanism has been suggested for neurological symptoms in SLE, further studies are needed to elucidate the mechanism. We propose that SLE should be considered as one of the differential diagnoses of SHM.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We measured the levels of 27 cytokines/chemokines and growth factors in cerebrospinal fluid (CSF) from 42 patients with sporadic amyotrophic lateral sclerosis (ALS), 12 patients with lower motor neuron disease (LMND), and 34 control patients with non-inflammatory neurological diseases (OND), using a multiplexed fluorescent bead-based immunoassay. Among cytokines/chemokines elevated in ALS, CCL2 and CXCL8 levels were negatively correlated with the revised ALS functional rating scale (ALSFRS-R) score, while CCL4 showed a positive correlation with ALSFRS-R score. CCL4 and CXCL10 showed negative correlations with disease progression rate. These chemokine alterations are assumed to somehow correlate with the clinical course of ALS.

DOI： 10.1016/j.jneuroim.2010.03.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Brain lesions are not uncommon in neuromyelitis optica (NMO) patients with anti-aquaporin-4 (AQP4) antibody; however, the appearance of these lesions is said to be different from that of those in Western patients with multiple sclerosis (MS). To clarify the similarities and dissimilarities of brain lesions in anti-AQP4 antibody-positive and -negative MS and NMO patients, we examined the presence of anti-AQP4 antibody in the sera of 148 consecutive patients fulfilling Poser's criteria for clinically definite MS, of whom 38 also met the revised NMO criteria, using an immunofluorescence method, and analyzed brain lesions by magnetic resonance imaging (MRI). Brain lesions fulfilling the Barkhof criteria were significantly more common in 121 patients without anti-AQP4 antibody than in 27 patients with anti-AQP4 antibody (57.0% vs. 33.3%, P=0.033), while the frequency of those that met the Paty criteria was not different between the two groups (74.4% vs. 73.5%). Ovoid lesions were detected more commonly in patients without anti-AQP4 antibody than in those with the antibody (72.3% vs. 48.2%, P=0.022). The anti-AQP4 antibody-positive patients had significantly more atypical brain lesions, such as extensive brain lesions, than the anti-AQP4 antibody-negative ones (18.5% vs. 1.7%, P=0.0023). Thus, although MS-like brain lesions are more common in anti-AQP4 antibody-negative patients than anti-AQP4 antibody-positive patients, approximately 30 to 50% of patients with anti-AQP4 antibody harbour brain MRI lesions indistinguishable from those present in typical MS patients, such as periventricular ovoid lesions, suggesting the existence of considerable overlap in brain MRI features between anti-AQP4 antibody-positive and -negative Asian patients. In the present study, NMO patients with brain lesions showed a significantly higher annualized relapse rate (P(corr)=0.017) and higher frequency of anti-AQP4 antibody (P(corr)<0.0001) than typical NMO patients without brain lesions, suggesting that development of brain lesions in NMO may reflect high disease activity and thus be a warning sign.

DOI： 10.1016/j.jns.2010.01.009

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

We report the case of a 30-year-old man who developed severe dysphagia owing to neuroborreliosis. He showed dysphagia, diplopia, hiccups, and walking difficulty Neurological examination revealed mild disturbance of consciousness, diplopia on left lateral gaze, left-side-dominant blephaloptosis, gaze-evoked horizontal nystagmus on left lateral gaze, mild bilateral muscle weakness, palatoplegia, dysphagia, dysarthria, and truncal ataxia An increased pharyngeal reflex caused dysphagia in this patient. An EEG revealed intermittent high amplitude slow wave activity. However, head MRI, blood count, serum chemistry, and cerebrospinal fluid examination showed no abnormality. Initially, brainstem encephalitis with unknown etiology was diagnosed. The hiccups, diplopia, and ptosis were improved by corticosteroid therapy, but other symptoms were refractory to corticosteroid therapy and IVIg. After these immunotherapies, anti-Borrelia IgG and IgM antibodies were found to be positive, and symptoms, including dysphagia, were improved by doxycycline and cefotaxime. Because the clinical symptoms of Borrelia infection are widely variable, neuroborreliosis should be considered in patients with brainstem encephalitis refractory to conventional immunotherapies.

DOI： 10.5692/clinicalneurol.50.265

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 35-year-old Japanese man was admitted to our hospital with recurrent meningoencephalitis of unknown etiology. He presented with fever, convulsions and loss of consciousness, which started at age 33. We diagnosed him with neuro-Sweet disease (NSD) based on human leukocyte antigen (HLA) B-54/Cwl positivity and neutrophilic infiltration into the dermis in a biopsied skin plaque. Intravenous methylprednisolone and oral prednisolone markedly improved his fever and CSF pleocytosis. Five years later he was again admitted to our hospital with high fever, oral aphthae and dull-red edematous plaques on the face and body. He was conscious, but he had neck stiffness, mild hyperreflexia in all limbs and an extensor plantar response. Laboratory tests revealed increased white blood cell, erythrocyte sedimentation rate (ESR) and C-reactive protein level. CSF analysis indicated mild pleocytosis. A skin biopsy from an edematous plaque revealed neurotrophils infiltrating the upper dermis. We treated him with intravenous methylprednisolone (1 g/day) for 3 days, followed by oral prednisolone (50 mg/day). His symptoms improved remarkably; however, he had recurrence of symptoms, such as fever, meningial irritation and oral aphtae, with attempted taper of prednisolone. We started treatment with dapsone (75 mg/day) in addition to prednisolone, and could taper oral prednisolone, without a relapse. However, because some mildly recurred with the tapering of dapson, we maintained dapsone treatment at 75 mg daily, added colchicine (1 mg/ day) and tapered only prednisolone. His symptoms were improved and no relapse has been observed. NSD is characterized by neurotrophic hyperactivation and infiltration of tissues. It is highly responsive to systemic corticosteroid therapy; however, some cases show frequent recurrences on tapering of corticosteroids. Dapsone is considered to prevent neurotrophic overactivity. In this case, dapsone was supposed to be effective to prevent reccurence of NSD upon tappering corticosteroids. Dapsone should be a therapeutic options for steroid-dependent NSD showing frequent recurrence.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2+/-8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.

DOI： 10.1007/s00401-009-0621-1

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

An 80-year-old man (patient 1) was admitted to our hospital with numbness of the right leg and weakness of the lower extremities, predominantly in the right leg, for 1 year previously. Neurological examination revealed moderate weakness without atrophy, and fasciculation in the bilateral lower extremities. No hyperreflexia was noted, and the plantar response was flexor. Neither bulbar palsy nor sensory disturbance was observed. Electromyography (EMG) showed a chronic neurogenic pattern, including giant motor unit potentials and reduced interference in all four limb muscles. MRI images of the cervical and lumbar spines showed severe age-related spondylosis. The clinical and laboratory findings led to a diagnosis of spinal progressive muscular atrophy. Motor paralysis progressed slowly for the following four years, culminating in respiratory failure. A 79-year-man, the younger brother of patient 1 (patient 2), suffered from gait disturbance for 3 years before the admission to our hospital. During the following 3 years, bilateral leg weakness developed, causing difficulty walking. Neurological examination revealed a diffuse mild weakness with atrophy and fasciculation in the bilateral lower extremities; the right deltoid muscle was also mildly weak. Mild hyperreflexia was also noted on the left side, and the plantar response was extensor on the left. EMG showed acute and chronic neurogenic patterns in the four limb muscles. Because the missense mutation c.377 T > C; p.L126S was found on exon 5 of the superoxide dismutase (SOD) 1 gene in this patient, a diagnosis of familial ALS was made. Eight patients reported as familial ALS with the SOD1L126S mutation, including the present cases, all developed an onset of weakness in the lower extremities, but showed few upper motor neuron signs. It is important to consider the possibility of this type of familial ALS in a case of spinal progressive muscular atrophy with late-onset and mild progression, if family history is positive.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

We reported a patient with immune-mediated encephalopathy showing refractory epilepsy and multiple brain lesions on MRI. The patient had high titers of anti-glutamic acid decarboxylase (GAD) antibody in sera and cerebrospinal fluid (CSF). A 36-year-old previously healthy woman was admitted to our hospital with onset of sudden generalized seizure that then persisted for one month. She had repeated epileptic attacks accompanied with loss of consciousness, and was refractory to valproic acid, zonisamide (200 mg/day) and phenobarbital (200 mg/day). Brain MRI showed multiple hyperintense lesions in predominantly bilateral frontal lobes, parietal lobes, occipital lobes and cingulate cortices. EEG showed epileptic activities (frequent sharp waves) in bilateral frontal regions. After admission, attacks disappeared through the administration of clonazepam (1.5 mg/day), though the patient remained slightly disoriented. As titers of anti-GAD antibody in sera and CSF were extremely high, we implemented plasma exchanges. After treatment, titers of anti-GAD antibody in sera and CSF decreased. The patient completely recovered to an alert state and the abnormal MRI lesions almost disappeared. Since GAD catalyzes production of gamma-aminobutyric acid (GABA), it is proposed that anti-GAD antibodies reduce synthesis of GABA or interferes with exocytosis of GABA in the nervous system. Anti-GAD antibodies are detected in some rare neurological disorders such as stiff-person syndrome. Recently, anti-GAD antibodies have been reported as implicated in cerebellar ataxia, palatal myoclonus, refractory epilepsy and limbic encephalitis. Epilepsy associated with the anti-GAD antibody is mostly pharmacoresistant temporal lobe epilepsy; with brain MRI showing no abnormality or only hippocampal sclerosis. It is very rare that brain MRI shows extensive abnormal lesions except in the hippocampus. This case suggests that anti-GAD antibodies could contribute to unexplained encephalopathy with extensive brain MRI lesions and drug-resistant symptomatic epilepsy.

DOI： 10.5692/clinicalneurol.50.92

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This is to report arterial spin-labeling (ASL) regional cerebral blood flow (rCBF) mapping findings in a case of corticobasal degeneration (CBD). A 68-year-old man gradually developed limb-kinetic apraxia, myoclonus, and rigidity in the left hand and was diagnosed as having CBD. Magnetic resonance imaging and single photon emission computed tomography revealed atrophy and decreased blood flow, respectively, in the right hemisphere, findings that were compatible with CBD. In addition, ASL rCBF mapping demonstrated asymmetrical hypoperfusion areas in locations typical for CBD, proving its potential usefulness for routine clinical differential diagnosis.

DOI： 10.1007/s11604-009-0382-8

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DOI： 10.1136/jnnp.2008.168260

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

This is to report arterial spin-labeling (ASL) regional cerebral blood flow (rCBF) mapping findings in a case of corticobasal degeneration (CBD). A 68-year-old man gradually developed limb-kinetic apraxia, myoclonus, and rigidity in the left hand and was diagnosed as having CBD. Magnetic resonance imaging and single photon emission computed tomography revealed atrophy and decreased blood flow, respectively, in the right hemisphere, findings that were compatible with CBD. In addition, ASL rCBF mapping demonstrated asymmetrical hypoperfusion areas in locations typical for CBD, proving its potential usefulness for routine clinical differential diagnosis.

DOI： 10.1007/s11604-009-0382-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00330-009-1511-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.

DOI： 10.1016/j.clineuro.2009.07.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS LTD  

There are two distinct subtypes of multiple sclerosis (MS) in Asians: opticospinal (OSMS) and conventional (CMS). OSMS has similar features to neuromyelitis optica (NMO) and half of OSMS patients have the NMO-Immunoglobulin G (IgG)/ anti-aquaporin-4 (AQP4) antibody. We reported that Helicobacter pylori (H. pylori) infection was significantly less common in CMS patients than controls. To reveal the immune responses to the H. pylori neutrophil-activating protein (HP-NAP) in Japanese MS patients, according to anti-AQP4 antibody status, sera from 162 MS patients, 37 patients with other inflammatory neurological diseases (OIND), and 85 healthy subjects were assayed for anti-H. pylori antibodies, anti-HP-NAP antibodies, and myeloperoxidase (MPO) by enzyme immunoassays. H. pylori seropositivity rates were significantly higher in anti-AQP4 antibody-positive MS/NMO (AQP4 + /MS) patients (19/27, 70.4%) than anti-AQP4 antibody-negative CMS (AQP4 - /CMS) patients (22/83, 26.5%). Among H. pylori-infected individuals, the anti-HP-NAP antibody was significantly more common in AQP4 + /MS and AQP4 - /OSMS patients than healthy subjects (36.8%, 34.6% versus 2.8%). Among the AQP4 + /MS patients, a significant positive correlation between anti-HP-NAP antibody levels and the final Kurtzke's Expanded Disability Status Scale scores was found, and MPO levels were higher in anti-HP-NAP antibody-positive patients than anti-HP-NAP antibody-negative ones. Therefore, HP-NAP may be associated with the pathology of anti-AQP4 antibody-related neural damage in MS/NMO patients.

DOI： 10.1177/1352458509348961

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC  

To categorize four types of sleep- and non-sleep-related hallucinations experienced by normal people and classify ghost or ghost-like stories by these categories. A total of 183 reliable tales of ghosts [41 from "Tohno Monogatari" (Tohno Folktales) and 142 from "Nihon Kaidan Shu" (Ghosts Tales of Japan)] are classified into hallucinations that are sleep-related hallucinations [hypnagogic hallucination-like (HyH) and REM sleep behavior disorder or somnambulism-like (RBDS) tales] and sleep-unrelated [vivid hallucination-like (VH) and highway hypnosis-like (HHy) tales] according to the criteria. Sixty to 70% of these tales can be classified into these four types of hallucinations. Further, sleep-related hallucinations increased from 17.0% to 36.6% in about 40 years. Our criteria will be useful to classify hallucinations experienced by normal people and to elucidate the mechanisms of these kinds of hallucinations experienced in neurodegenerative or psychological disorders.

DOI： 10.1037/a0017611

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background.-
Headache is common in Western patients with multiple sclerosis (MS), but its frequency has not been reported in Asian patients. In Asians, the opticospinal form of MS, showing similar characteristics to relapsing neuromyelitis optica in Westerners, is regarded as a different subtype from conventional MS.
Objectives.-
The aim of this study was to clarify the frequency of primary and chronic secondary headaches in Japanese patients with MS and the factors associated with the emergence of such headaches.
Methods.-
We investigated 127 consecutive patients with clinically definite MS. Frequencies of primary and chronic secondary headaches were compared according to clinical subtype, administration of interferon beta, and anti-aquaporin-4 antibody status.
Results.-
The frequency of patients with primary and chronic secondary headaches at the time of interview was 64/127 (50.4%); the frequency of migraine was 26/127 (20.4%) and that of tension-type headache was 38/127 (29.9%). The frequencies of patients with primary and chronic secondary headaches and migraine without aura after the onset of MS were higher in patients undergoing interferon beta therapy than in those not on the therapy (42.4% vs 23.4%, P &lt; .05 and 15.1% vs 4.3%, P = .05, respectively). There were no significant differences in the frequency of primary and chronic secondary headaches based on clinical subtype of MS. However, among patients not receiving interferon beta, the occurrence of migraine with aura after the onset of MS was significantly higher in patients with anti-aquaporin-4 antibody than in patients without the antibody (13.3% vs 0.0%, P &lt; .05).
Conclusions.-
In Japanese patients with MS, the frequency of primary and chronic secondary headaches, especially migraine, was higher than in the general Japanese population. Administration of interferon beta was related to a higher frequency of primary and chronic secondary headaches, especially migraine without aura, irrespective of clinical subtype of MS.

DOI： 10.1111/j.1526-4610.2009.01427.x

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DOI： 10.1177/1352458509106613

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

Erectile dysfunction, dysuria, photophobia, and chronic cough developed insidiously in a 49-year-old man from his third decade. Severe difficulty of urination resulted in intermittent catheterization. He had six family members who had suffered similar autonomic symptoms with or without motor deficits. He presented asymmetrical tonic pupils, a neurogenic bladder, and mild sensory impairment in the distal parts of the bilateral lower limbs without orthostatic hypotension and motor deficits. Nerve conduction studies revealed mild axonal changes with slightly reduced conduction velocities in the lower limbs. His left pupil over-responded to instillation with 0.125% pilocarpine. Functional bladder tests showed an atonic bladder, suggesting postganglionic parasympathetic involvement. Autonomic evaluation for sympathetic components including head-up tilt, beat to beat responses to Valsalva's maneuver, cardiac MIBG imaging, plasma catecholamine levels and sweat tests were all normal. A genetic test disclosed a heterozygous mutation of myelin protein zero (MPZ); p.Thr124Met. Selectively distributed dysautonomia in this pedigree may indicate parasympathetic postganglionic components including the ganglion as the primary target of this mutated MPZ in the autonomic nervous system.

DOI： 10.5692/clinicalneurol.49.582

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The mediodorsal thalamic nucleus (MD) has strong connectivity to the limbic systems and frontal lobe. The aim of this study was to determine whether the mediodorsal thalamic nucleus influences seizure induction by electrical stimulation in the rat frontal cortex. MATERIALS AND METHODS: Juvenile male rats (n=7) were used in the experiment. At postnatal day 28 (P28), stainless steel skull screws were inserted for stimulating cortices. Depth-stimulating electrodes were stereotaxically inserted into the MD of the bilateral thalamus. Electrical stimulation, which produces afterdischarges, was applied to the frontal cortices once/day for four consecutive days from postnatal day 38. Additional conditioning electrical stimulation to the bilateral MD was fixed at 0.1 mA, and the stimulus frequency was increased from 0 Hz, 1 Hz, and 5 Hz to 10 Hz. All seven rats were stimulated with those frequencies by rotation every other day. The data of animals with 0 Hz MD stimulation were defined as controls. Afterdischarge thresholds and durations were measured at each frequency. RESULTS: Seizures were accompanied by bilateral tonic-clonic convulsions and cortical spikes. Seizure behaviors were not different among the groups and there were no statistically significant differences in the cortical afterdischarge (AD) thresholds between animals with MD stimulations and controls in all frequencies. In the cortical AD durations, there were also no statistically significant differences between animals with MD stimulation and controls although the mean duration at 10-Hz stimulation was less than the control animals. CONCLUSION: These results indicated that thalamic MD stimulation might not suppress epileptic seizure induction. Further studies are needed to analyze other stimulus parameters, altered stimulus locations, and different test paradigms.

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DOI： 10.3174/ajnr.A1562

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DOI： 10.1111/j.1600-0404.2008.01099.x

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1212/WNL.0b013e3181a0fe74

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DOI： 10.1177/1352458508097923

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Two cases of spinocerebellar ataxia type 14 (SCA14) with a G128D mutation in the protein kinase C gamma gene (PRKCG) without a definite family history have been reported previously. Here, we describe the first familial cases of SCA14 with a G128D mutation in PRKCG. Among three family members, the chief complaints varied and included ataxic gait, cervical dystonia, and positional vertigo. Moreover, retinal degeneration and facial muscle weakness were observed, although these are not expected to be present in SCA14. Cerebral blood flow evaluation using single photon emission computed tomography (SPECT) also differed among family members. It is possible that patients with the G128D mutation suffering from SCA14 may sometimes be classified as unaffected due to the varying clinical signs among family members.

DOI： 10.1016/j.clineuro.2008.09.013

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DOI： 10.1177/1352458508096871

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

Focal cortical dysplasia (FCD) is of increasing interest as a cause of focal epilepsy. We aimed to determine whether the existence of FCD influences the epileptogenicity induced by electrical kindling stimulation of the cortices. We created an FCD rat model by focal contact of a frozen metal probe on the scalp immediately after birth. To produce afterdischarges (ADs), electrical stimulation was applied to the frontal cortices once daily for 20 consecutive days from postnatal day 38 (P38). Thresholds and durations of ADs were measured. Brains were exposed and examined histologically at P58. We observed mild FCD, which consisted of disorganized cortices with extra sulci; however, there was no statistical difference in the thresholds or durations of ADs between FCD rats and control animals. These results suggest that FCD might not influence vulnerability to epileptogenicity, at least in some patients with mild FCD.

DOI： 10.1016/j.jocn.2008.04.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-beta protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment enhanced caspase-4 and -9 activities in I143T-mutant PS1-transfected cells, while hydrogen peroxide treatment enhanced caspase-4, -8 and -9 activities in G384A-mutant PS1-transfected cells, indicating diverse apoptosis-promoting effects of PS1 gene mutations. In addition, treatment with a beta-secretase inhibitor or gamma-secretase inhibitor significantly attenuated the effects of the PS1 mutants on caspase-3/7 activation and recovered cell viability. Our present data suggest that these PS1 mutants accelerate the activation of initiator caspases and promote apoptosis, which may be associated, at least in part, with amyloid-beta production.

DOI： 10.3233/JAD-2009-0989

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.

DOI： 10.3233/JAD-2009-0990

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is associated with airway allergy and hyperIgEaemia, suggesting the involvement of immunological processes. In this study we aimed to clarify the changes in various cytokines/chemokines in cerebrospinal fluid (CSF) from JMADUE patients. We simultaneously measured 17 cytokines/chemokines in sera and CSF from 6 patients with JMADUE before treatment and from 14 patients with cervical spondylosis (CS) as a disease control (mean age at examination 23+/-7 and. 57+/-16 years, respectively), using a fluorescent bead-based immunoassay. We also assayed CSF from a JMADUE patient before and after plasma exchanges. In sera, only an increase of MIP-1beta (CCL3) in the JMADUE patients had a marginal significance as compared with the CS patients. In the CSF, IFN-gamma and MIP-1beta (CCL3) were significantly elevated in JMADUE patients compared with controls (1.5 and 2-fold increases, respectively), while no other cytokines/chemokines showed any significant differences. Moreover, the upregulated cytokines decreased after plasma exchanges in accord with improvement of distal upper limb weakness. The intrathecal upregulation of proinflammatory Th1 cytokines/chemokines, such as IFN-gamma and MIP-1beta (CCL3), in the CSF of JMADUE patients indicates the possible involvement of intrathecal immunological processes in this condition.

DOI： 10.1016/j.jns.2008.07.020

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We report the first non-Caucasian case of facial onset sensory and motor neuronopathy (FOSMN) syndrome partially responding to various immunotherapies. A 55-year-old man had first felt paresthesia on his right cheek at age 45. This gradually extended to the scalp. Paresthesia of bilateral fingers and dysphagia appeared 6 years later. On admission, facial sensory impairment and bulbar palsy were found. There were no sensory or motor deficits evident in any limb, except for decreased deep tendon reflex and vibratory sensation. Videofluorography (VF) revealed decreased pharyngeal clearance. The sensory nerve action potential (SNAP) amplitudes of median and ulnar nerves were decreased. Intravenous immunoglobulin therapy and plasma exchange ameliorated his dysesthesia and dysphagia after several weeks, and resulted in improvements in VF and SNAP abnormalities. These observations suggest that FOSMN syndrome maybe, in part, immune-mediated.

DOI： 10.1016/j.jns.2008.07.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BENTHAM SCIENCE PUBL LTD  

The amyloid cascade hypothesis is well known hypothesis describing the pathogenesis of Alzheimer&apos;s disease (AD). On the basis of this hypothesis, inhibition of amyloid beta-protein (A beta) generation and aggregation, enhancement of extracellular A beta removal, and A beta vaccination are currently under investigation. Intracellular A beta may be even more important than extracellular A beta since intraneuronal A beta accumulation commonly precedes extracellular A beta deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular A beta such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. Recently, we have reported that cytosolic A beta 42 accumulation leads to p53 mRNA expression and p53-related apoptosis. It was also reported that a novel chaperone protein, A beta-related death-inducing protein (AB-DIP), regulates nuclear localization of intracellular A beta 42. Therefore, intraneuronal A beta represents an alternative therapeutic target. While inhibition of A beta production and anti-A beta immunotherapies are likely to attenuate both intraneuronal and extracellular A beta toxicity, more specific anti-intraneuronal A beta therapies should be useful. The focus of this article is to review the pathogenic mechanisms involving intracellular A beta and advocate intracellular A beta as an important therapeutic target in AD.

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DOI： 10.1177/1352458508097818

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Among 22 consecutive patients with myelitis, of unknown etiology, and atopic diathesis (atopic myelitis) who from April 2002 to March 2006 had been studied in our clinic, 5 (23%) showed focal amyotrophy in one or two limbs. These 5 patients were subjected to combined clinical, electrophysiological, neuroimaging and immunological studies. Ages were 18 to 58-years-old (average 39). Four showed amyotrophy of unilateral or bilateral upper limbs while one showed amyotrophy in both thighs. All patients showed on-going denervation potentials in the affected muscles, while motor conduction study including F wave was normal except for in one patient who showed prolonged F wave latency in one nerve. Two had localized high signal intensity lesions involving anterior horns on spinal cord MRI and three showed abnormalities suggesting pyramidal tract involvement on motor evoked potentials. All had a present and/or past history of atopic disorders and specific IgE against common environmental allergens, such as mite antigens and cedar pollens, and four showed mild eosinophilia, all of which were compatible with atopic myelitis. When clinical and laboratory findings were compared between atopic myelitis with (n=5) or without focal amyotrophy (n=17), the former showed a significantly higher frequency of present and past history of asthma (80% vs. 24%, p=0.0393) and tended to have higher EDSS scores (3.8+/-1.6 vs. 3.1+/-1.4). Two patients showed mild to moderate improvements after immunotherapies such as methylprednisolone pulse therapy or plasma exchange, while two recovered with low dose corticosteroids and one without treatment had a gradually progressive course. Although atopic myelitis preferentially involves the posterior column of the cervical spinal cord, it is possible that anterior horn cells are affected in some cases of atopic myelitis, especially in patients with asthma. This suggests a possible link between atopic myelitis and Hopkins syndrome (asthmatic amyotrophy).

DOI： 10.1016/j.jns.2008.01.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

PURPOSE: Focal cortical dysplasia (FCD) is thought to be an important cause of intractable epilepsy. However, its epileptogenicity remains unclear. Therefore, we created a novel rat model by freeze lesioning during the late embryonic stage to verify whether FCD influences seizure activities. METHODS: At 18 days postconception, a frozen probe was placed on the left scalp of a Sprague-Dawley rat embryo through the uterus wall. For 40 consecutive days from postnatal day 38 (P38), electrical kindling stimulation was applied to the frontal lobes of male rat pups. Afterdischarges (ADs) were measured in both the cortex and hippocampus. Brain tissues were examined by immunohistochemistry. RESULTS: All brains from prenatally freeze-lesioned rats displayed severe disorganization of the cortical layers with randomly oriented dendrites/axons. In addition, heterotopic cortices were observed in 42.1% of cases. ADs in the cortex and hippocampus were significantly prolonged in freeze-lesioned rats compared with those in sham-operated and control rats. FCD rats also revealed early development of hippocampal kindling and spontaneous cortico-hippocampal spikes, even in the chronic EEG recordings. Immunoreactivities for N-methyl-D-aspartate receptor (NMDAR) subunit 2B and glutamate/aspartate transporter in the lesions were significantly enhanced compared with the nonlesioned side, even in the absence of electrical stimulation. After electrical stimulation, NMDAR1 and 2B were markedly upregulated not only in the FCD, but also in the hippocampus. CONCLUSIONS: Prenatal freeze lesioning of the brain produces a severe neuronal migration disorder, closely mimicking human FCD. Our model suggests that FCD is associated with vulnerability to epilepsy, and may augment hippocampal epileptogenicity.

DOI： 10.1111/j.1528-1167.2008.01558.x

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 56-year-old woman attended our hospital because of acute severe (thunderclap) headache. Neurological examination was normal and no abnormality was found on head CT or by cerebrospinal fluid examination. A few days later, she experienced a recurrence and suffered a seizure in her left upper and lower extremities. On neurological examination, she had conjugate deviation of the eyes toward the right side and left lower limb paralysis with Chaddock sign. MRI showed multiple hyperintense lesions in the bilateral occipital and parietal lobes, predominantly in the subcortical white matter at the right side on T2-weighted and FLAIR images. We diagnosed posterior reversible encephalopathy syndrome (PRES) because the ADC map showed a vasogenic edema pattern (increased ADC values in the hypodense lesions on diffusion-weighted image). Her blood pressure was normal and there were no underling diseases. As MRA showed vasoconstriction especially in bilateral posterior cerebral arteries, we initiated a therapy with a Ca-channel blocker. On follow-up MRI, the hyperintense lesions on T2-weighted and FLAIR images had almost disappeared, and vasoconstriction was also improved on MRA. This case suggested that cerebral vasoconstriction could underlie both thunderclap headache and PRES.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We herein report an autopsy case of a 63-year-old man with amyotrophic lateral sclerosis (ALS) who developed "ampulla cardiomyopathy." At the age of 56, he noticed a progressive weakness in his right upper extremity. One year later, a progressive weakness of the left upper extremity began. Dropped head and progressive weakness of the lower extremities emerged at the ages of 61 and 62, respectively. Intravenous immunoglobulin and plasma-exchange therapies did not improve his weakness. At the age of 63, one month before his death, he was hospitalized due to aspiration pneumonia. A tracheostomy was performed to secure his airway. Four days after the operation, an ST elevation of his electrocardiogram was incidentally found on the ECG monitor. An echocardiogram revealed diffuse hypokinesia of the wall of the left ventricle except in the basal portion, which is the typical finding of "ampulla cardiomyopathy." Wall motion of the left ventricle improved and his circulatory condition was stabilized after treatment, but his condition thereafter worsened again and he died 3 weeks later. An autopsy examination revealed diffuse fibrosis and degeneration of the cardiomyofibers. Neuropathological examination revealed neuronal cell loss, Bunina bodies and skein-like inclusions in the hippoglossal nuclei. In the thoracic spinal cord, degenarated anterior horn cells were seen and macrophage permeation in the corticospinal tract were shown by CD68 immunostaining. Therefore, the final neuropathological diagnosis was ALS. This report is the first autopsy case of ALS complicated with "ampulla cardiomyopathy."

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS LTD  

There are two distinct subtypes of multiple sclerosis (MS) in Asians, optic-spinal (OSMS) and conventional (CMS). In OSMS, severe spinal cord lesions are characteristic while brain lesions are scant. We sought to clarify atypical brain lesions in OSMS by neuroimaging and pathological studies. For brain MRI, 124 consecutive Japanese patients with clinically definite MS based on Poser criteria were enrolled, 57 with OSMS and 67 with CMS. Ten autopsied cases (seven OSMS and three CMS) were studied pathologically. Although the frequency of brain lesions fulfilling Barkhof criteria was significantly higher in CMS than in OSMS, periventricular linear lesions along with the anterior portion of the corpus callosum and the lateral ventricles were significantly more common in OSMS than in CMS. Pathologically, periventricular lesions in CMS extended deeply into the white matter, while those in OSMS were confined to periventricular areas. T cell infiltration in lesions was prominent in CMS but not in OSMS. Although severe axonal loss and cavity formation were commonly seen in periventricular and spinal cord lesions in OSMS, lymphocytic infiltrates and vessel wall thickening were observed only in the latter. Thus, we suggested that anterior periventricular linear lesions without ovoid ones are characteristic of OSMS.

DOI： 10.1177/1352458507084085

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

There are two distinct subtypes of multiple sclerosis (MS) in Asians: optic-spinal (OSMS) and conventional (CMS). Longitudinally extensive spinal cord lesions (LESCLs) extending over three or more vertebral segments are characteristic of patients with OSMS, yet in Asians, one-fourth of CMS patients also have LESCLs. To clarify the distinction between LESCLs in OSMS and CMS, and to characterize the relationship between the presence of LESCLs and brain magnetic resonance imaging (MRI) findings, we studied 142 patients with clinically definite MS of relapsing-remitting onset and 12 patients with primary progressive MS (PPMS) by MRI of the whole spinal cord and brain. The former was diagnosed by Poser criteria, including 57 with OSMS, 67 with CMS and 18 with brainstem-spinal form of MS, while the latter by McDonald criteria. The presence of LESCLs throughout the entire clinical course was significantly more common in OSMS patients than in CMS patients, while brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) were significantly more common in CMS patients than OSMS patients. LESCLs in OSMS patients most frequently affected the upper to middle thoracic cord, with either holocord or central gray matter involvement. By contrast, 70% of LESCLs in CMS patients predominantly affected the peripheral white matter of the mid-cervical cord. LESCLs in patients with PPMS also showed preferential involvement of the peripheral white matter of the mid-cervical cord. One-third of OSMS patients had neither LESCLs nor Barkhof brain lesions more than 10 years after disease onset, and showed significantly milder disability than OSMS patients with LESCLs. These findings suggest that LESCLs are heterogeneous between OSMS and CMS patients, and that there are distinct subtypes of MS in Japanese, according to clinical and MRI findings.

DOI： 10.1016/j.jns.2007.09.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disease characterized by progressive heterotopic endochondral osteogenesis with great-toe malformations. A 617G > A (R206H) mutation of the activin A type 1 receptor gene (ACVR1) has been found in all previously reported patients with FOP. Thus, this is one of the most specific of all disease-associated mutations. We report here on a 62-year-old man with slowly progressive FOP and a novel mutation in ACVR1. He developed difficulty in moving his shoulder since age 10 years due to contraction of the shoulder joint. The symptoms progressed slowly, and he could not walk at age 36 years and was bedridden at 55 years. He also showed rigid spine, baldness, sensorineural hearing loss, and hypodactyly accompanied by abnormal ectopic ossification. Analysis of ACVR1 and its cDNA revealed that the patient is heterozygous for a mutation, 1067G > A (G356D). Typing of SNPs located in the approximately 0.5-Mb region spanning ACVR1 and its neighbor genes suggested that 1067G > A is a de novo mutation. These results give a clue to better understanding of FOP as well as of the mild clinical symptoms in the patient.

DOI： 10.1002/ajmg.a.32151

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

RATIONALE AND OBJECTIVES: A method of estimating and mapping the cortical damage resulting from neurodegenerative diseases based on diffusion-weighted imaging was recently proposed. We improved on this method to visualize the cortical damage in Alzheimer's disease (AD) in the lateral and medial aspects of the cerebral hemispheres and to provide anatomic references. MATERIALS AND METHODS: Damage in the cerebral cortex was estimated based on diffusivity in the subcortical white matter according to a previously published method. A map of subcortical mean diffusivity (MD) was superimposed on the corresponding anatomic image so that the spatial extent of the abnormality could be anatomically localized. The right and left hemispheres were separated to evaluate the medial and lateral aspects of each hemisphere. This method was applied to 10 healthy subjects and 11 AD patients. MDs within 20 cortical regions were visually evaluated and statistically compared between AD and healthy subjects at a significance level of P < .01. RESULTS: In addition to the involvement of the lateral aspects of the bilateral parietal and temporal lobes and clear sparing of the bilateral pericentral regions that were previously reported, significant MD elevation was observed in the medial aspects of the right frontal, bilateral parietal, and right temporal lobes. The extent of MD abnormalities was easily identified by the background anatomic image. CONCLUSIONS: Results suggested that AD damage in the lateral and medial cerebral cortex can be visualized with an anatomic reference using our method.

DOI： 10.1016/j.acra.2007.10.008

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 72-year-old man with eosinophilic myositis (EM). At age 71 he noticed a painful nodule in his left calf. A biopsy (first biopsy) showed marked infiltration of mononucleated cells and necrotic muscle fibers. Several phagocytosed fibers were also seen. He was diagnosed as having myositis. The painful nodule disappeared spontaneously. At age 72, he again had a painful nodule, but this time in his right calf; again, this disappeared spontaneously on the first admission. Just after discharge, he noted painful nodules in the left thigh and right anterior tibial muscles and was again admitted (second admission). Neurological examination revealed mild proximal-dominant weakness in all four extremities but no other abnormalities. Laboratory studies showed elevated creatine kinase (CK) level (38,803 U/l; normal 62-287) and positive Jo-1 antibody, but no eosinophilia. Needle electromyography of the limb muscles showed myogenic patterns. Magnetic resonance imaging of the lower limbs demonstrated several T2-high and gadolinium (Gd)-enhanced lesions. Muscle biopsy (second biopsy) from the left quadriceps femoris showed marked infiltration of eosinophils; he was diagnosed as having EM. Administration of prednisolone was initiated at 60 mg/day and then gradually tapered. After starting treatment with steroids, his muscle weakness gradually ameliorated, CK level dramatically decreased, and the nodules disappeared. Clinically, the patient had developed localized nodular myositis (LNM), but pathologically it was EM without peripheral blood eosinophilia and positive Jo-1 antibody that is occasionally found in polymyositis (PM). Thus, this patient demonstrated overlapping characteristics of EM, LNM, and possibly PM, suggesting that a common mechanism underlay these conditions. As discussed, the involvement of eosinophils in three inflammatory myopathies was indicated.

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DOI： 10.1136/jmg.2007.053942

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.47.0846

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Aging may alter the motor functions of the basal ganglia and cerebellum; however, no previous neuroimaging study has investigated the effect of aging on the functional connectivity of the motor loops involving these structures. Recently, using fMRI with a parametric approach and structural equation modeling (SEM), we demonstrated a significant functional interaction within the basal ganglia-thalamo-motor (BGTM) loop during self-initiated (SI) finger movement in young normal subjects, whereas cerebro-cerebellar (CC) loop was mainly involved during externally triggered (ET) movement. We applied this method to 12 normal aged subjects (53-72 years old) in order to study the effect of age on BGTM and CC loops. Compared with the functional connectivity seen in young subjects, SEM showed decreased connectivity in BGTM loops during SI task, decreased interaction in the CC loop during ET task, and increased connectivity within motor cortices and between hemispheres during both types of tasks. These results suggest an age-related decline of cortico-subcortical connectivity with increased interactions between motor cortices. Aging effects on SI and ET movements are probably caused by functional alterations within BGTM and CC loops.

DOI： 10.1016/j.neuroimage.2007.04.027

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 73-year-old man with SPG4. From aged 53 he had diabetes mellitus and at 64 he developed spastic paraparesis and urinary disturbance. At 70 years, he began to walk with a stick and noted abnormal sensations in bilateral feet. There was no relevant family history. Moderate spasticity with mild muscle weakness, markedly brisk tendon reflex with pathological reflexes, and mildly abnormal sensation in bilateral lower extremities, and markedly spastic gait were found. MRI showed mild C4-C7 spondylosis and L4-5 disk protrusion but no abnormality of the corpus callosum. Nerve conduction and needle EMG studies revealed various abnormalities in distal (MCV, SCV) and proximal (F-wave) peripheral nerves, but no neurogenic changes in limb muscles. We found a missense spastin gene mutation (1726T>C) that causes Leu534Pro substitution. This spastin gene mutation was novel in Japanese, but has been reported in an Italian family. The present case's neuropathy might be related to diabetes mellitus, because SPG4 is generally not associated with neuropathy. However, recent studies suggest that SPG4 patients sometimes have subclinical neuropathy, and longer disease duration may contribute to peripheral neuropathy. Further study of clinical characteristics associated with the Leu534Pro mutation will be necessary.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the 11 patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-1b than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.

DOI： 10.1093/brain/awm027

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Inhibition of aggregation of amyloid p-protein (AP) and promotion of extracellular AM removal are known as potent therapeutic tools for Alzheimer's disease (AD). While, the importance of Af342 accumulating in neurons has recently been suggested, and we have reported that A/42 accumulating in the neurons moves into the nucleus, activating p53 mRNA expression and leading to apoptosis (Ohyagi et al, FASEB J, 2005). Moreover, intraneuronal Ap is reported to induce mitochondrial dysfunction via binding ABAD, synaptic pathology, and inhibition of proteasome. Thus, it is an alternative therapeutic tool to decrease the levels of A342 and p53 proteins in AD neurons. We established a human neuroblastoma (SH-SY5Y) cell culture system in which AV peptide is artificially accumulated in cytosol. We have found that apomorphine hydrochloride promotes degradation of intracellular AM and p53 attenuating oxidative stress-induced apoptosis. Using a proteasome activity assay method, one of the mechanisms is thought to be activation of proteasome. Similar anti-apoptotic effect was observed in the primary cultured neurons. Apomorphine hydrochloride is now used as a dopamine agonist for Parkinson's disease or an anti-ED drug in western countries, but also may be one of the candidate drugs to inhibit neuronal death in AD.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Amyloid beta-protein ending at 42 (Abeta42) is the major peptide deposited in Alzheimer's disease (AD) brain. In immunocytochemical studies, formic acid treatment is used to dramatically enhance Abeta immunoreactivity. Recently, Abeta42 has been reported to accumulate in AD neurons. Since heating is known to enhance intracellular protein immunoreactivity, we used an autoclaving protocol to enhance intraneuronal Abeta42 immunoreactivity. Using this protocol, both anti-Abeta42 N-terminal and C-terminal antibodies, but not anti-Abeta40 C-terminal antibody, labeled AD neurons. Moreover, formic acid treatment counteracted such effects of autoclaving. Thus, intraneuronal Abeta42 accumulation may have been underestimated by conventional methods using formic acid only.

DOI： 10.1016/j.jneumeth.2006.06.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We measured the intracellular productions of IFNgamma, IL-2, IL-4, IL-13 and TNFalpha in peripheral blood CD4(+) and CD8(+) T cells from 21 amyotrophic lateral sclerosis (ALS) patients, 14 disease controls (DC) with spinocerebellar degeneration and 16 healthy controls (HC). Only the percentages of CD4(+)IL-13(+) and CD8(+)IL-13(+) T cells were significantly higher in ALS patients than in DC and HC. The CD4(+)IL-13(+) T cell percentages showed a significant negative correlation with the revised ALS functional rating scale scores and significant positive correlation with the disease progression rate, suggesting that IL-13 contributes to ALS.

DOI： 10.1016/j.jneuroim.2006.10.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

We report a case of O'Sullivan-McLeod syndrome in a 59-year-old man, who had experienced slowly progressive weakening of both hands since he was 20 years of age. Mild hyperIgEemia and eosinophilia were present. Nerve conduction studies revealed reduced F wave-evoked frequencies for the median and ulnar nerves. Intravenous immunoglobulin (IVIG) at a dose of 400 mg/kg/day was given for 5 days. After IVIG, the muscle weakness of the distal upper extremities improved together with increased F wave-evoked frequencies. These effects lasted for a few months. These observations suggest that immune-mediated neural damage partially contributes to O'Sullivan-McLeod syndrome.

DOI： 10.2169/internalmedicine.46.6221

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ASSOC UNIV RADIOLOGISTS  

RATIONALE AND OBJECTIVES: White matter (WM) abnormality in Alzheimer's disease (AD) has been less well characterized than cortical damage. We studied the spatial distribution of the subcortical WM abnormality using diffusion-weighted magnetic resonance imaging (DWI). MATERIALS AND METHODS: Twenty-one AD patients and seven healthy, elderly subjects were included. DWIs were obtained using a cerebrospinal fluid (CSF)-nulled pulse sequence to reduce the partial volume contamination of CSF signal. Diffusivity in the subcortical WM voxels was mapped onto the cortical surface using original software so that the spatial distribution of subcortical WM damage, which was visualized as an area of increased diffusivity, could be viewed in a three-dimensional map. The damages in the lateral surface of the bilateral cerebral hemispheres were visually evaluated, and severities of the damages in five brain regions were compared with each other. In addition, the severity of the damage in each region was correlated with patient's mini-mental state examination (MMSE) score. RESULTS: In both hemispheres, clear sparing of the pericentral regions and predominant involvement of the parietal and temporal regions were revealed with statistical significance (P < .05, respectively). Marginal correlation (P < .05 uncorrected for multiple comparisons) was observed between the damage severity in the bilateral frontal and right temporal regions and patient's MMSE score. CONCLUSION: We demonstrated a subcortical WM abnormality over the parietal and temporal regions with clear sparing of the pericentral region using our mapping method, which supported the hypothesis that the subcortical WM abnormality in AD originates in Wallerian degeneration.

DOI： 10.1016/j.acra.2006.09.042

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We report a case of a 46-year-old Japanese woman with hereditary progressive dystonia with marked diurnal fluctuations and dopa-responsive dystonia (HPD/DRD). She developed difficulty in walking at the age of 44 years due to bradykinesia as well as hand tremors, muscle rigidity, increased tendon reflexes and mild dystonia in the lower extremities, all of which responded remarkably to low doses of levodopa (150 mg/day). Biopterin and neopterin concentrations in the cerebrospinal fluid (CSF) were decreased. Analysis of the guanosine 5'-triphosphate cyclohydrolase I (GCH1) gene revealed a novel mutation (W53X) in one allele. The GCH1 activity that was expressed in mononuclear blood cells was almost half the normal value (usually 2-20% of the normal value (39.0+/-9.2 pmol/ml) in patients with HPD/DRD). The relatively conserved GCH1 activity that is expressed in stimulated peripheral blood mononuclear cells may be related to the late clinical symptoms in this patient.

DOI： 10.1016/j.clineuro.2005.10.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We studied the role of fasudil, a selective Rho-kinase inhibitor, in experimental autoimmune encephalomyelitis (EAE). Both parenteral and oral administration of fasudil prevented the development of EAE induced by proteolipid protein (PLP) p139-151 in SJL/J mice. Specific proliferation of lymphocytes to PLP was significantly reduced, together with a downregulation of interleukin (IL)-17 and a marked decrease of the IFN-gamma/IL-4 ratio. Immunohistochemical examination also disclosed a marked decrease of inflammatory cell infiltration, and attenuated demyelination and acute axonal transaction. These results may provide a rationale of selective blockade of Rho-kinase by oral use of fasudil as a new therapy for multiple sclerosis.

DOI： 10.1016/j.jneuroim.2006.06.027

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ASSOC UNIV RADIOLOGISTS  

RATIONALE AND OBJECTIVE: Brain tissue damage in frontotemporal dementia (FTD) has never been systematically studied using diffusion-weighted imaging (DWI). We studied FTD patients using DWI to determine whether microstructural changes in white matter can be detected in vivo. MATERIALS AND METHODS: Thirteen FTD patients and 15 aged healthy subjects were studied. Mean diffusivity (MD) abnormalities in 28 white matter regions were visually evaluated. In addition, MD values in 10 white matter regions relative to that in the ipsilateral postcentral gyrus were measured. The results were compared between healthy subjects and FTD patients. RESULTS: The visual rating resulted in a significant MD elevation in FTD patients in the bilateral high superior frontal gyri, right orbitofrontal gyrus, bilateral anterior temporal lobes, and left middle temporal lobe (P < .01, respectively). Relative MD comparison revealed a significant MD elevation in FTD patients in the bilateral high superior frontal gyri, bilateral orbitofrontal gyri, and bilateral anterior temporal lobes (P < .05 after Bonferroni correction, respectively). CONCLUSION: Our results demonstrated white matter MD abnormalities in FTD patients. It was suggested that the observed white matter MD abnormalities are secondary to damage in the overlying cortex.

DOI： 10.1016/j.acra.2006.08.009

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1212/01.wnl.0000244489.65670.9f

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DOI： 10.1212/01.wnl.0000238510.84932.82

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BENTHAM SCIENCE PUBL LTD  

Amyloid beta-protein (Abeta) plays a pivotal role in Alzheimer's disease (AD). Therapeutic strategies inhibiting Abeta aggregation and promoting extracellular Abeta removal are currently advocated. Here, we review recent literature on intracellular Abeta, especially intranuclear Abeta, and its associated molecules. We also discuss alternative therapeutic strategies to inhibit intracellular Abeta-related pathogenesis.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 53-year-old woman with probable Bassen-Kornzweig syndrome. Her parents were a consanguineous marriage. At two years of age, she developed night blindness. During her childhood she had severe diarrhea that disappeared in adulthood. At 26 years of age, she was diagnosed as having retinitis pigmentosa and her visual acuity became worse thereafter. She noted tremor in the right hand at 37 years of age, gait ataxia at 42, and developed tremor in the bilateral lower extremities at 48. On admission, bilateral visual disturbance, resting and postural tremor, moderately poor coordination, mild distal dominant sensory impairment, an absence of tendon reflex in all four extremities, moderate to severe gait ataxia, and positive Romberg sign were found. Muscle rigidity and akinesia were not observed. Intelligence and muscle power were normal and pathological reflexes were absent. Acanthocytes were found in blood. Serum chemistry showed remarkable decreases in total cholesterol (54 mg/dl, normal 180-220), triglyceride (0 mg/dl, normal 30-150), beta-lipoprotein (3 mg/dl, normal 190-500), apoA-1 protein (66 mg/dl, normal 105-184), apoA-2 protein (11 mg/dl, normal 26-46), apoB protein (0 mg/dl, normal 38-104), apoC-2 protein (1.1 mg/dl, normal 1.2-6.4), vitamin A (297 ng/ml, normal 431-1,041), and vitamin E (0.19 ng/dl, normal 0.75-1.41). While, a marked increase in PIVKA II (703 mAU/ml, normal<40) due to a decrease in vitamin K was found. She was thus diagnosed as having Bassen-Kornzweig syndrome or hypo-betalipoproteinemia. Although brain MRI was normal, single-photon emission CT (SPECT) showed mildly decreased perfusion in the left parietal cortex and right striatum. Motor nerve conduction velocities were normal, but sensory nerve action potentials were not evoked in all four extremities. Surface EMG recorded on the right radial extensor and flexor carpi muscles at rest showed a 4.5 Hz tremor. Vitamin replacement therapy with vitamin A (10,000 IU/day), E (200 mg/day), and K (10 mg/day) was initiated. Several days after treatment, amplitude of resting tremor ameliorated mildly. Clonazepam was administered (0.5 mg/day) for further treatment. After one-month of treatment, vitamin A (656 ng/ml) and E (0.39 mg/dl) levels were elevated and PIVKA II level (29 mAU/ml) decreased. Only a mild right hand tremor remained, but sensory impairment and gait ataxia were not changed. The cause of Bassen-Kornzweig syndrome is a deletion of the microsomal triglyceride transfer protein (MTP) gene. While, familial hypo-betalipoproteinemia, due to a mutation of apolipoprotein B gene, is known to show the same phenotype. Because of the patient's refusal of genetic examination, which disease she has cannot be conclusively determined. Intention tremor was reported in Bassen-Kornzweig syndrome. However, her 4.5 Hz tremor was also present at rest, which resembled resting tremor in Parkinson's disease. Pathophysiology of Bassen-Kornzweig syndrome is known to be due to hypo-vitaminosis. Decreased [18F]-dopa uptake in striatum of patients with long-term hypo-vitamin E has been reported in PET study. Mild hypoperfusion was found in the striatum of the present cases: indicating that her tremor was associated with striatonigral damage. Thus, careful observation of extrapyramidal signs is necessary in abeta- or hypo-betalipoproteinemia.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

To clarify the role of myeloperoxidase (MPO) in multiple sclerosis (MS), we measured serum MPO levels in 86 Japanese patients with relapsing remitting MS, 47 with opticospinal MS (OSMS) and 39 with conventional MS (CMS), and 85 healthy subjects by sandwich enzyme immunoassays and analyzed relationships with clinical features. We found a significant increase in serum MPO in OSMS patients at relapse and remission, and in CMS patients at remission compared with controls. By logistic regression analysis, the clinical variable associated with high level of MPO at remission in OSMS patients (higher than the mean+/-2 S.D. of healthy controls) was only Kurtzke's Expanded Disability Status Scale (EDSS) score in blood sampling (p=0.0245); that is, a greater EDSS scores in the high MPO group, whereas in CMS none were associated. The results of our study suggest that MPO levels in remission are related with severe tissue destruction in OSMS.

DOI： 10.1016/j.jneuroim.2006.05.026

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

An improved method for Southern DNA and Northern RNA blotting using the Mupid-2 Mini-Gel System is described. We get sharp and clear bands in Southern and Northern blotting after only 30 min short gel electrophoresis instead of the several hours large gel electrophoresis of conventional methods. The high electrical voltage with a pulse-like current of the Mupid-2 Mini-Gel System also allows reduction of the amount of formaldehyde, a harmful reagent, from the gel running buffer in RNA blotting. This minor modification of DNA and RNA blotting technique enables us to perform the complete experimental procedure more quickly economically in less space, than conventional Southern and Northern blotting, as well as using an extremely small amount of formaldehyde in RNA blotting.

DOI： 10.1016/j.jbbm.2006.04.005

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 76-year-old man began to mistake his family for another person, and fall asleep easily while watching TV. He was treated with donepezil but without any effect. He was referred to our hospital on June. On admission, his consciousness was alert. Cranial nerves and motor functions were normal, but pathological reflexes were positive bilaterally. Serological examinations revealed high titers of antibodies against thyroglobulin and TPO, and antibody against alpha-enolase was positive. Total protein level in CSF was 40 mg/dl and cell counts were normal. On MRI, localized symmetrical lesions were observed in bilateral pallidum to genu of internal capsule. SPECT revealed hypoperfusion areas in bilateral striate bodies and frontal lobes. Neuropsychological examinations indicated impairment of executive function and procedural memory. The diagnosis of Hashimoto's encephalopathy was made and we treated the patient with oral prednisolone 60 mg/day followed by gradual tapering. After the treatment, clinical symptom as well as neuropsychological function improved. Neuropsychological impairment in this case was probably due to the disconnection of the thalamo-frontal projection. This case provides interesting suggestions that Hashimoto's encephalopathy may present with vasculitic infarctions in bilateral MCA perforators, and that this disease should be included in one of the differential diagnoses of cerebral infarctions of unknown etiology.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

To investigate cytokine/chemokine changes in amyotrophic lateral sclerosis (ALS), we simultaneously measured 16 cytokine/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony stimulating factor [G-CSF], macrophage chemoattractant protein-1 [MCP-1], and macrophage inflammatory protein-1beta) in cerebrospinal fluid (CSF) and sera from 37 patients with sporadic ALS and 33 controls using a multiplexed fluorescent bead-based immunoassay. We also conducted immunohistochemical analyses from 8 autopsied ALS cases and 6 nonneurologic disease controls as well as cell culture analyses of relevant cytokines and their receptors. We found that concentrations of G-CSF and MCP-1 were significantly increased in ALS CSF compared with controls. In spinal cords, G-CSF was expressed in reactive astrocytes in ALS cases but not controls, whereas G-CSF receptor expression was significantly decreased in motor neurons of spinal cords from ALS cases. Biologically, G-CSF had a protective effect on the NSC34 cell line under conditions of both oxidative and nutritional stress. We suggested that G-CSF has potentially neuroprotective effects on motor neurons in ALS and that downregulation of its receptor might contribute to ALS pathogenesis. On the other hand, MCP-1 correlated with disease severity, which may aggravate motor neuron damage.

DOI： 10.1097/01.jnen.0000232025.84238.e1

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DOI： 10.1212/01.wnl.0000223835.51268.12

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The basal ganglia and cerebellar loops are known to participate differently in self-initiated (SI) and externally triggered (ET) movements. However, no previous neuroimaging studies have illustrated functional organization of these loops in vivo. Here, we aimed to functionally visualize these loops during motor execution using functional magnetic resonance imaging (fMRI) with structural equation modeling (SEM). Twelve normal subjects (24-29 years old) were scanned while performing five different frequencies of sequential left finger movements using either SI or ET movements. Random effect analysis combined with a parametric approach revealed a significant positive linear dependence of cerebral activation upon movement rate in the right Put, GPi, VL, SMC and SMA during SI tasks. During ET tasks, significant positive linear relationships were found in the right SMC, VPL, left CB and DN, whereas tendency for linear relationships was seen in the right PMv. SEM further showed significant interactions within the right basal ganglia-thalamo-motor loop during SI tasks. In contrast, there were significant interactions within the entire right cerebral hemisphere-left cerebellar loop involving CB, DN, VPL, PMv and SMC during ET tasks. Therefore, our modeling approach enabled identification of different contributions of the motor loops of basal ganglia and cerebellum to SI and ET tasks during motor execution.

DOI： 10.1016/j.neuroimage.2005.12.032

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 56-year-old man with adult-onset Sydenham chorea. Since January 2003, he had often troubled other persons, and in October 2003, following an episode of fever in August of the same year, he noticed left shoulder joint pain and involuntary movements of his limbs, especially on the left side. These involuntary movements gradually worsened and he became unable to converse due to psychiatric symptoms. On admission, neurological examination revealed dementia, emotional incontinence, abnormal behavior and chorea in four limbs. Brain MRI disclosed swelling of bilateral caudate heads that was more marked on the right side. Hypermetabolism in bilateral caudate nuclei, especially on the right, was found on FDG-PET study, which was compatible with his left side-dominant chorea and might reflect inflammation as a nature. A gallium scintigram demonstrated excess accumulations in the plural joints of his extremities, which gradually decreased in parallel with joint pain relief. The present case was diagnosed as Sydenham chorea, because of the presence of arthritis, chorea, fever, increased erythrocyte sedimentation rate and elevated CRP. We believe that this is a first report of adult-onset Sydenham chorea accompanied with psychiatric symptoms.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 50-year-old woman developed gait disturbance and hypersomnia over a period of a month. General physical examination revealed axillary lymph node swelling. On neurological examinations she was fully orientated but hypersomnic; short term memory disturbance, horizontal gaze evoked nystagmus and ataxic gait were observed. Electroencephalography disclosed a tendency for easily decreasing vigilance with delta activities but normal dominant rhythm. Cerebrospinal fluid examinations showed increased protein amounts (109 mg/dl) without either pleocytosis or atypical cells. An echogram of the breasts revealed a tiny mass in the left side. Pathological studies on a biopsied lymph node and the mass in her left breast showed a mammillary duct carcinoma. Brain MRI was normal, and no anti-neuronal antibody was detected in sera by two dimensional immunoblotting using human brain crude antigens. She was diagnosed as having paraneoplastic limbic encephalitis (PLE) associated with breast cancer. Over 42 hours polysomnography showed long total sleep time (TST) with a high ratio of sleep stage 1/TST and no REM sleep abnormalities; this resembled a thalamic-hypothalamic damaged sleep pattern. At first she was treated with plasma exchanges, but no improvement was observed. Hormonal and chemotherapies produced partial resolution of her neurologic symptoms and there were signs of reduction of the breast mass. Most reported PLE cases with hypersomnia have been associated with testicular cancer and anti-Ma antibodies. The present case is an extremely rare example manifesting hypersomnia without either testicular cancer or anti-Ma antibody. Since anti-tumor therapy successfully ameliorated her neurologic symptoms, cell-mediated immunity against a common tumor and neuronal antigens rather than hormonal immunity may have played a role in the development of her PLE.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 47-year-old woman with progressive multifocal leukoencephalopathy (PML). She was a carrier of HTLV-I virus, and developed subacute right hemiparesis and marked motor aphasia. She had a malignant lymphoma in the left neck and basal cell carcinoma in the right inguinal region. Three months after the onset, she became unable to walk because of the right leg weakness or to speak because of motor aphasia. Magnetic resonance imaging (MRI) revealed multifocal T2-high lesions in the white matter of the left frontal lobe, and a brain biopsy revealed demyelinating pathology. A biopsy of the left parotid gland revealed a diffuse pleomorphic type large B cell lymphoma. Although anti-HTLV-I antibody was positive in the serum and cerebrospinal fluid (CSF), no adult T-cell leukemia (ATL) cells were found in the blood or CSF. The patient was then admitted to our hospital. Neurological examinations revealed severe motor aphasia, mild sensory aphasia/cognitive impairment, right hemiplegia, mild right hemihypesthesia, limb-kinetic apraxia in the left hand, idiomotor apraxia, agraphia, perseveration, marked spasticity and brisk tendon reflex in four extremities, and positive bilateral pathological reflexes. MRI showed multifocal T2-high lesions mainly in the cerebral white matter, predominantly in the left hemisphere, and partly in the cerebral cortex. No gadolinium enhancement was found. In addition, 99mTcECD-SPECT showed a broad decrease in cerebral blood flow (CBF) in the cortex. Anti-HTLV-I antibody was positive but anti-HIV antibody was negative in serum. ATL cells were found in 1-3% of the peripheral white blood cells after admission. CSF examination revealed that the cell count (1/microl), protein level (24 mg/dl), and IgG index (0.4) were all normal. However, the myelin basic protein level (321 pg/ml; normal < 102) was increased, JC virus DNA was detected by PCR, and anti-HTLV-I antibody (x 8) was detected in CSF. The regulatory region of the JC virus DNA in the CSF was partly deleted; immunostaining with anti-JC virus protein antibodies revealed the existence of JC virus in biopsied brain specimens, and these findings were consistent with PML. Her symptoms such as motor aphasia, cognitive dysfunction and left hemiparesis were subacutely progressive, and she developed akinetic mutism two weeks after admission. Since the efficacy of cytosine arabinoside for PML has been reported, she was administered 80 mg/day of the drug for five days. After treatment, her communication function was mildly improved but the efficacy was transient. Since it has been reported that HTLV-I, as well as HIV, activates the JC virus promoter and its proliferation, the latent infection of HTLV-I in the central nervous system (CNS) in this case might have stimulated the JC virus proliferation, promoting lesion extension over the cerebral cortex. There have been only a few reports of broad decreases in CBF by SPECT in PML patients. Further MRI and SPECT studies on PML patients are therefore necessary to evaluate the significance of HTLV-I in promoting the JC virus infiltration into the CNS.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 52-year-old woman with primary progressive multiple sclerosis (PPMS) presenting with chronic progressive memory impairment. From a couple of years prior to admission, she had developed impairment of her short-term memory. For example, she forgot her nephew's name, and spoke the same phrases again and again. She also sometimes forgot to turn off her gas stove and forgot things she bought in shops. Moreover, her mental activity gradually decreased and she became apathetic. However, she did not note her memory impairment, and had no hallucinations. She was admitted to our hospital on 20 May, 2003 because donepezil had been ineffective for treating her memory impairment. Neurologically, she showed bilateral horizontal gaze nystagmus, mild limb ataxia on the left and mildly ataxic gait. Neuropsychological examinations showed mildly impaired cognitive function, e.g., MMSE 25/30, WAIS-R full IQ 69 and especially in verbal short memory, which may represent temporal lobe dysfunction. Moreover, Benton's visual memory test revealed marked visual short-term memory impairment, while impaired performance on a Kana picking up test suggested mild to moderate attention impairment, which could have represented frontal lobe dysfunction. Brain MRI showed multiple T2-high plaque lesions close to the bilateral lateral ventricles, and bilateral optic nerve lesions enhanced by gadolinium. Also, spinal cord MRI showed a gadolinium enhanced lesion at Th5 on the left. Cerebral spinal fluid (CSF) examination showed normal cell count and protein level, and undetectable oligoclonal bands (OCB), but an elevated IgG index (1.1, normal < 0.85). Visual evoked potentials (VEPs) showed prolonged P100 latency bilaterally, indicating subclinical optic nerve lesions. She was thus diagnosed as having PPMS according to McDonald's diagnostic criteria for MS. 99mTc Single photon emission computed tomography (SPECT) showed a decreased cerebral blood flow (CBF) in the bilateral frontal and temporal lobes, which was consistent with her clinical features. PPMS patients generally present with chronic progressive spastic paraparesis and/or cerebellar ataxia. Cognitive impairments observed in PPMS are generally thought to be due to white matter lesions, i.e., subcortical dementia. However, some recent reports have shown MS patients with short-term memory impairment (antegrade amnesia) similar to cortical dementias such as Alzheimer's disease (AD). In such MS cases, visual short-term memory impairment seems characteristic of their cognitive impairment compared to AD cases. As well, the present case showed visual memory impairment as evaluated by Benton's memory test. Parietal and frontal lobes are reported to be important for verbal and visual working memory, respectively. Thus, in the present case, decreased CBF in the frontal and temporal lobes, which could have been due to a disconnection between cortices and subcortices caused by the white matter lesions, is consistent with the type of her cognitive dysfunction, i.e., notable visual memory impairment. PPMS may thus be an important disease as a differential diagnosis for chronic progressive dementia. Further neuropsychological and functional imaging studies will be necessary to achieve a better understanding of the mechanisms of cognitive impairment in PPMS.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We here report a 45-year-old man with left arm focal dystonia induced by golf. He was a swimming instructor. From 35 years of age, he swung a golf club for 4 hours everyday. At 37 years of age, he noted difficulties in moving left arm when swinging, and developed involuntary movement of left arm toward his back thereafter. His involuntary movement was exacerbated even in several years after stopping both golf and swimming. Neurologically, simultaneous contraction was observed in left triceps and biceps muscles and his left arm dropped when raising arm to front. A 'sensory trick' was also observed. Thus, he was diagnosed as having a rare focal dystonia, and its clinical characteristics and course were basically different from those of 'yips', a focal dystonia that is characterized by anxiety and distal dominant dystonia presenting only on golf. Magnetic resonance imaging (MRI), FDG-positron emission CT (FDG-PET), C11-Raclopride PET and 99mTc-single photon emission CT (SPECT) revealed no abnormality in cerebral cortex and basal ganglias. However, motor evoked potentials (MEPs) were not evoked bilaterally when magnetic stimulation was applied on primary motor cortex. On functional MRI (fMRI), 40 seconds raising left arm task-induced activation in the right primary motor, supplementary motor, and premotor areas was apparently decreased, while left motor areas, the normal side, were reasonably activated. Motor-associated areas are generally overactivated by task in focal dystonia patients whereas excitability in primary motor area is decreased in idiopathic generalized dystonia. Therefore, dystonia of the present case appears to be similar to focal dystonia clinically but may partly have a mechanism similar to idiopathic generalized dystonia as shown in the fMRI studies.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The existence of peripheral neuropathy after chronic exposure to polychlorinated biphenyls (PCBs) is still controversial because studies concerning the effects of PCBs on the peripheral nervous system are rare. Objective: The purpose of this study was to determine the correlation between neurological signs and symptoms and the concentration of serum PCBs. Materials and methods: Neurological data collected from the results of a nationwide health examination of 450 male and 557 female Yusho victims (chronic PCB poisoning) exposed more than 36 years ago were compared with recent measurements of the serum PCB concentration and patterns. Results: The frequency of sensory disturbance detected by neurological examination was significantly higher in the group of officially acknowledged victims (male, P = 0.014
female, P = 0.001) than in age-matched controls. Significant differences were not observed between the serum PCB patterns and the neurological findings, but the serum PCB concentration was significantly higher in the group with decreased tendon reflex in officially and non-officially acknowledged female Yusho victims (male, P = 0.994
female, P = 0.014). Conclusion: These results suggest that the long half-life of PCBs and their accumulation in fatty tissue can lead to persistent mild impairment of the peripheral nervous system even long after exposure. © 2004 Japanese Society for Investigative Dermatology.

DOI： 10.1016/j.descs.2005.03.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: The existence of peripheral neuropathy after chronic exposure to polychlorinated biphenyls (PCBs) is still controversial because studies concerning the effects of PCBs on the peripheral nervous system are rare.
Objective: The purpose of this study was to determine the correlation between neurological signs and symptoms and the concentration of serum PCBs.
Materials and methods: Neurological data collected from the results of a nationwide health examination of 450 mate and 557 female Yusho victims (chronic PCB poisoning) exposed more than 36 years ago were compared with recent measurements of the serum PCB concentration and patterns.
Results: The frequency of sensory disturbance detected by neurological examination was significantly higher in the group of officially acknowledged victims (mate, P = 0.014; female, P = 0.001) than in age-matched controls. Significant differences were not observed between the serum PCB patterns and the neurological findings, but the serum PCB concentration was significantly higher in the group with decreased tendon reflex in officially and non-officially acknowledged female Yusho victims (mate, P = 0.994; female, P = 0.014).
Conclusion: These results suggest that the long half-life of PCBs and their accumulation in fatty tissue can lead to persistent mild impairment of the peripheral nervous system even tong after exposure. (C) 2004 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.descs.2005.03.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Expanded CUG triplet repeats carrying mRNA seem to be responsible for myotonic dystrophy type 1 (DM1). To study the pathogenesis of DM1, we constructed a DM1 cell culture model using a PC12 neuronal cell line and screened flavonoids that ameliorate this mRNA gain of function. The expanded 250 CTG repeat was subcloned into the 3'-untranslated region of the luciferase gene yielding a stable transformant of PC12 (CTG-250). The cytotoxicity of CTG-250 was evaluated by intracellular LDH activity, and the cis-effect by luciferase activity. To find agents that alter CTG-250 toxic effects, 235 bioflavonoids were screened. An increased cis-effect and cytotoxicity were found when CTG-250 was treated with nerve growth factor to induce differentiation. Western blotting with anti-caspase-3 antibody suggested that cell death was caused by apoptosis. Screening analysis confirmed that a flavone (toringin), an isoflavones (genistein and formononetin), a flavanone (isosakuranetin), and DHEA-S prevent both the cytotoxicity and cis-effect of CTG-250 and that a flavanone (naringenin), isoflavone (ononin), and xanthylatin strongly inhibit the cis-effect of CTG repeats. In conclusion, we found that this neuronal cell line, which expresses the CUG repeat-bearing mRNA, showed cis-effects through the reporter gene and neuronal death after cell differentiation in vitro. However, some flavonoids and DHEA-S inhibit both the cis-effect and cytotoxicity, indicating that their chemical structures work to ameliorate both these toxic effects. This system makes it easy to evaluate the toxic effects of expanded CTG repeats and therefore should be useful for screening other DM1 treatments for their efficacies.

DOI： 10.1016/j.bcp.2004.10.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

DOI： 10.1096/fj.04-2637fje

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

DOI： 10.1096/fj.04-2637fje

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記述言語：英語   出版者・発行元：SPRINGER HEIDELBERG  

DOI： 10.1007/s00415-004-0555-4

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 29-year-old woman with benign congenital nemaline myopathy is reported. She did not walk until the age of one year and seven months. Although she acquired the ability to run, she ran very slowly. She first noticed the progression of weakness of the limbs at age 21, and it worsened gradually. On admission, she showed moderate weakness in the face, neck, and four limbs. Serum creatine kinase was elevated to 218 U/l. Needle electromyography showed giant and polyphasic motor unit potentials with a reduced reference pattern in the four limbs diffusely. In muscle biopsy, about 10% of fibers had many small vacuoles, and half of them were rimmed. Modified Gomori trichrome stain revealed nemaline rods in about 20% of both type I and type II fibers. Fibers with large diameter and atrophic ones showed increased acid phosphatase activity. Type I fibers were small, and type II fibers numbered only 2%. We diagnosed her illness as a congenital nemaline myopathy that began in infancy and progressed in adulthood. The increased autophagic activity probably caused the progression of muscle weakness. Moreover, the presence of both nemaline rods and rimmed vacuoles may have contributed to the development of diffuse neurogenic changes seen in electromyography.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Visual agnosia has been well studied by anatomical, neuropsychological and neuroimaging studies. However, functional changes in the brain have been rarely assessed by electrophysiological methods. We carried out electrophysiological examinations on a 23-year-old man with associative visual agnosia, prosopagnosia and cerebral achromatopsia to evaluate the higher brain dysfunctions of visual recognition. Electrophysiological methods consisted of achromatic, chromatic and category-specific visual evoked potentials (CS-VEPs), and event-related potentials (ERPs) with color and motion discrimination tasks. Brain magnetic resonance imaging revealed large white matter lesions in the bilateral temporo-occipital lobes involving the lingual and fusiform gyri (V4) and inferior longitudinal fasciculi due to multiple sclerosis. Examinations including CS-VEPs demonstrated dysfunctions of face and object perception while sparing semantic word perception after primary visual cortex (V1) in the ventral pathway. ERPs showed abnormal color perception in the ventral pathway with normal motion perception in the dorsal pathway. These electrophysiological findings were consistent with lesions in the ventral pathway that were detected by clinical and neuroimaging findings. Therefore, CS-VEPs and ERPs with color and motion discrimination tasks are useful methods for assessing the functional changes of visual recognition such as visual agnosia.

DOI： 10.1016/j.jns.2004.03.024

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 23-year-old man with mitochondrial encephalomyopathy. At 21 years of age, he noted speech distubance. Since his dysarthria did not improve thereafter, he was admitted to our hospital. On admission, he showed mild gynecomastia. Neurological examination revealed mild decrease in performance IQ in WAIS-R, mild scanning speech, mild left hearing disturbance, mild to moderate muscle weakness in proximal four extremities, mild bilateral limb ataxia, and mild to moderate truncal ataxia. While, no brisk deep tendon reflex, pathological reflex, aberrant muscle tonus, sensory disturbance, retinopathy, myoclonus or autonomic disorder was found. Serum levels of lactate (23.2 mg/dl, normal≤18.7) and pyruvate (1.23 mg/dl, normal&lt
0.94) were elevated, and serum lactate levels were markedly elevated (118.1 mg/dl) after 15-minute exercise (15 Watts/minute). CSF levels of lactate (31.2 mg/dl, normal≤12.5) and pyruvate (1.48 mg/dl, normal&lt
0.75) were also elevated. Head MRI showed mild cerebral and cerebellar atrophy, but 1H-MRS showed no lactate peak. Moreover, muscle biopsy from left biceps muscle showed lots of ragged-red fibers, and he was thus diagnosed as having mitochondrial encephalomyopathy. However, nt3243 mutation of mitochondria DNA was not present. Next, we confirmed gynecomastia by mammography, and checked serum levels of estrogens. Mildly decreased estradiol (19.9 pg/ml
normal, 20-59), normal estrone (24.0 pg/ml, normal&lt
30.0) and mildly increased estriol (6.03 pg/ml, normal≤5.0) were found. While, the serum levels of cortisol, dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were all within normal limits. Since the steroid hormone synthesis system and hypothalamus-pituitary system seem to be normal, 16α-hydroxylase that converts estradiol to estriol may be upregulated. While, aromatase (P-450arom) is well known to convert androgens to estrogens. In addition, 16α-hydroxylase and P-450arom convert DHEA-S to estriol. Since it is recently reported that P-450arom is considerably expressed in muscle tissues as well as fat tissues and that muscle tissue may be a major organ to produce estrogens in men and postmenopausal women, estriol production may be increased in the present patient's muscle. Although hypogonadism due to hypothalamus-pituitary disorders was sometimes reported, there have been no reports that suggest an increased estrogen production in skeletal muscles in mitochondrial encephalomyopathies. Recently, estrogen has been known to protect muscle fibers from oxidative damages due to exercise. Thus, it is of potential that estrogens increased locally in muscle tissues of the patients with mitochondrial encephalomyopathies protect muscle fibers from oxidative damage due to mitochondrial dysfunction.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 58-year-old woman suffered from stiffness, swelling, rubor and muscle pain in the extremities one month after she climbed a mountain in Kyushu, an island in southern Japan. On admission, mild proximal weakness was present in the extremities. Her range of motion in the extremities was limited due to firm skin and subcutaneous stiffness which was similar to scleroderma. She showed peripheral blood eosinophilia and hypergammaglobulinemia as well as a high erythrocyte sedimentation rate. An IgM antibody against Borrelia afzelii was positive. MRI of the skeletal muscles demonstrated enhancing fascia around the biceps brachii muscle, and a biopsy specimen revealed perivascular infiltration of mononuclear cells within the hypertrophic fascia. Eosinophilic infiltration was absent. We treated the patient with prednisolone, doxycycline and amoxicillin, which alleviated the symptoms. This is the first report to show that Borrelia afzelii was involved in eosinophilic fasciitis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG  

Amyopathic dermatomyositis (ADM) is characterized by the typical cutaneous features of dermatomyositis and minor involvement of the skeletal muscles. A 50-year-old woman had fever, reddening and pain in the distal part of all four limbs, and cutaneous findings such as Gottron's papules and periorbital heliotrope. She showed no muscle weakness or atrophy, and her serum creatine kinase was within the normal range. Electromyography showed no myopathic pattern. Magnetic resonance imaging (MRI) recorded abnormal hyperintensity in the fascia and muscle of the tibialis anterior. A biopsy from the tibialis anterior muscle showed fasciitis and mild myopathic changes with focal perivascular infiltration. This patient also presented with interstitial pneumonitis, although evaluation for malignancy was negative. With steroid therapy, her symptoms and MRI abnormality disappeared within 2 months. This case is therefore considered to be a variant of ADM, presenting as dermato-fasciitis.

DOI： 10.1007/s10067-003-0824-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Bone marrow transplantation (BMT) is accepted as an efficient therapy for X-linked adrenoleukodystrophy (ALD). To clarify the mechanisms of this treatment, we examined the effects of hematopoietic cell transplantation (HCT) in an ATP-binding cassette, subfamily D, member 1 (ABCD1) knock out mice and co-culture of ALD patient fibroblasts with normal cells. We treated ABCD1 knock out mice with HCT using lacZ-transgenic mice as donors, which enabled us to detect donor-derived cells. We also examined the effects of co-culturing a normal microglia cell line (N9) with ALD fibroblasts. beta-Galactosidase (beta-GAL) activity was higher in spleen, lung and kidney than in liver, brain and spinal cord of the recipient ABCD1 knock out mice. HCT reduced the accumulation of very long chain fatty acid (VLCFA) in those tissues. The reduction of the VLCFA ratio was significant in spleen and lung; tissues with higher beta-GAL activity. ABCD1 was detectable in spleen from HCT mice. Co-culture of ALD fibroblasts with normal fibroblast cells reduced VLCFA accumulation in ALD cells. This effect was not observed when the cells were co-cultured while separated by a filter membrane. Our data suggest that supplying normal cells for ABCD1 knockout mouse by HCT corrects metabolic abnormalities in ALD tissues through a cell-mediated process. The correction requires direct cell-to-cell contact for recovering normal cell function.

DOI： 10.1016/j.jns.2003.11.006

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by hereditary motor and sensory neuropathy (HMSN). He had experienced complex partial seizures (CPS), which started with a nausea-like feeling, followed by loss of consciousness and automatism, since he was 6 years old. The frequency of attacks was at first decreased by phenytoin. However, attacks increased again when he was 18 years old. On admission, neurological examination showed mild weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory sensation in his legs. Ten people in four generations of his family showed a history of epilepsy in the autosomal dominant inheritance form. His younger sister and mother had a history of epilepsy accompanied with pes cavus, hammer toe, weakness of toe and finger extension and mildly impaired vibratory sensation as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in which several mutations were reported in patients with familial lateral temporal lobe epilepsy, showed no specific mutation in this family. On consecutive video-EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto-temporal region when he showed automatism, and then a generalized slow burst activity was detected when he lost consciousness. For his seizures, TLE with secondary generalization was diagnosed. In the nerve conduction study, delayed nerve conduction, distal motor latency and decreased amplitudes of the compound muscle action potentials (CMAP) of bilateral peroneal nerves were observed, indicating the existence of mild axonal degeneration. Based on these data, we consider that this family to be a new phenotype of autosomal dominant TLE accompanied by motor and sensory neuropathy.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.

DOI： 10.1093/hmg/ddg343

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

It has been reported that diffusion-weighted imaging (DWI) can detect white matter degeneration in the Alzheimer's disease (AD) brain. We hypothesized that imaging of the slow diffusion component using high b value DWI is more sensitive to AD-related white matter degeneration than is conventional DWI, and therefore we studied the effects of high b value on lesion-to-normal contrast and contrast-to-noise ratio (CNR). Seven AD patients and seven age-matched normal subjects were studied with full-tensor DWI at three different b values (1000, 2000, and 4000 s/mm(2)) without changing echo time or diffusion time, and the mean diffusivities in the parietal and occipital regions were measured. Statistical analyses revealed that use of higher b values significantly improves both lesion-to-normal contrast and CNR. We concluded that high b value DWI is more sensitive to AD-related white matter degeneration than is conventional DWI.

DOI： 10.1016/S1053-8119(03)00342-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG  

Dysferlin is a newly identified sarcolemmal protein related to Miyoshi myopathy and limb-girdle muscular dystrophy. Although its function is still unknown, it is inferred from the presence of C2 domains and a transmembrane domain in its sequence that dysferlin may be expressed or located not only at the sarcolemma but also in other membranous organelles to interact with Ca(2+). Tubular aggregates (TAs) are derived from sarcoplasmic reticulum (SR) and found in various myopathies, especially in those related to disturbed intra-sarcoplasmic Ca(2+) homeostasis. To clarify the expression of dysferlin in TAs and the relationship among TA formation, dysferlin expression, and endoplasmic reticulum (ER) stress, we examined the expression of dysferlin and other sarcolemmal proteins by immunohistochemistry in 12 muscle biopsy specimens with TAs from 11 cases of periodic paralysis and 1 case of myalgia/cramps syndrome. Moreover, the expression of glucose-regulated protein 78 (GRP78) and GRP94, which are up-regulated under ER stress, was also examined by immunohistochemistry and immunoblotting. TAs showed strong expression of dysferlin. GRP78 and GRP94 were also intensely expressed in TAs. Total amounts of GRP78 and GRP94 were significantly increased in muscles with TAs compared with normal controls. These results indicate that muscles with TAs seem to be under ER stress, probably resulting from disturbed intra-sarcoplasmic Ca(2+) homeostasis. Strong expression of dysferlin in TAs suggests the possibility that it is located not only at the sarcolemma but also in the SR, at least in the pathological conditions.

DOI： 10.1007/s00401-003-0686-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

This study reports a novel presenilin 1 (PS1) gene mutation in a Japanese family with Alzheimer's disease (AD). Two patients developed progressive memory disorder with disorientation around 50 years of age and showed myoclonus with frequent tonic-clonic seizures several years later. Direct sequencing of the proband's PS1 gene revealed a novel mis-sense mutation (leucine-to-valine at residue 250 (L250V)). This mutation was found in both patients, but not in a normal family member or normal Japanese control subjects. Thus, L250V is a novel PS1 gene mutation responsible for familial AD (FAD) in Japan.

DOI： 10.1016/S0022-510X(02)00466-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG  

Abnormal proteolysis may be involved in the motor neuron degeneration of amyotrophic lateral sclerosis (ALS). Although several studies of the ubiquitin-proteasome system in ALS have been reported, the endosome-lysosome system has not been investigated in detail. To clarify the association of neurodegeneration with the endosome-lysosome system in ALS, we examined the pathological expression of cysteine proteases such as cathepsins B, H and L and an aspartate protease, cathepsin D, in the anterior horns of 15 ALS cases and 5 controls. In the ALS cases, cathepsin B immunoreactivity was preferentially decreased in the lateral parts of the anterior gray horns compared with the controls. Its immunoreactivity was increased in the cytoplasm of both shrunken and pigmented neurons but was weak in the neurons containing Bunina bodies. In addition, reactive astrocytes were also immunolabeled with cathepsin B. Cathepsin H and cathepsin L were detected in the cytoplasm of a small number of shrunken and pigmented neurons. Cathepsin D immunoreactivity was strong in the cytoplasm of all motor neurons. The immunoreactivity of cathepsins H, L and D was not significantly different between control and ALS cases. Western blot analysis showed that the 25-kDa activated form of cathepsin B was down-regulated in ALS. Our results suggest that cathepsin B is involved in the motor neuron degeneration in ALS.

DOI： 10.1007/s00401-002-0667-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

A 62-year-old man who developed akinetic mutism with delayed white matter demyelination after hypoxia was treated with hyperbaric oxygen (HBO). HBO in the subacute period markedly improved the patient's activity in daily life, cognitive function and organization on EEG. 1H-MRS showed a recovery of aerobic metabolism of the neurons. However, dementia and cerebral atrophy slowly progressed despite HBO treatment. Thus, HBO had a beneficial effect on the activity of depressed neurons but did not improve the prognosis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Previous positron emission tomography (PET) studies have shown widespread hypometabolism in the brain of advanced MSA but the time course of these metabolic abnormalities is largely unknown. In order to clarify the principal disease processes in multiple system atrophy (MSA) in the early stage, we investigated regional cerebral glucose metabolism (rCMGglc) and nigral dopaminergic function in nine patients with early stage of MSA using [(18)F]fluorodeoxyglucose (FDG) and 6-L-[(18)F]fluorodopa ((18)F-Dopa) positron emission tomography (PET) (two men and seven women; age, 59.3+/-5.4 years; disease duration, 29.7+/-14.6 months). The rCMRglc in the early MSA patients significantly decreased in the cerebellum, brainstem, and striatum compared with that in nine normal subjects. A significant correlation was found between the severity of autonomic dysfunction and rCMRglc within the brainstem. The severity of extrapyramidal signs also correlated with the decline of F-Dopa uptake but not that of rCMRglc within the striatum. The degree of atrophy on MRI has correlated with neither the clinical symptoms nor rCMRglc at the cerebellum and the brainstem. Our PET studies demonstrated widespread metabolic abnormalities except for the cerebral cortex in the brain of MSA even in the early stage. The hypometabolism in the brainstem was tightly linked to the autonomic dysfunction. Not the striatal dysfunction but the nigral damage may be responsible for the extrapyramidal symptoms in early MSA.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

In Japan, neuropsychological assessment of dementing illnesses has been done mainly using Mini-Mental State Examination (MMSE) and a revised version of Hasegawa Dementia Scale (HDS-R). However, because of a lack of appropriately designed test domains, early detection of senile dementia and/or cognitive impairment is hardly possible, even if using these batteries. This paper is to introduce a Japanese Version of RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) which was originally developed by Randolph and revised by us. The entire battery of Japanese Version RBANS took less than 30 minutes to administer, and yielded scaled scores for five cognitive domains such as immediate memory, visuospatial/constructional ability, language, attention, and delayed memory. On RBANS, abnormal cognitive decline in the older adult was much easily detected, being compared to MMSE and HDS-R: 52 normal volunteer subjects ranging from 24 to 80 years old showed a significant (p < 0.05 on t test) impairment of delayed and immediate memories due to ageing. The aged (60-79) subjects with average scores of MMSE and HDS-R being over 25, significantly showed impairment of both immediate memory (list and story learnings) and delayed memory (list, story and figure recalls). The present data suggest that the Japanese Version RBANS is useful for both detecting and characterizing early dementia, and should be widely utilized for a neuropsychological screening battery in the clinical practice throughout Japan.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We here report a 44-year-old woman with Charcot-Marie-Tooth disease (CMT) type 1 who showed severe bilateral phrenic nerve palsy (PNP). She had chronic progressive distal dominant muscle weakness and atrophy since early in her second decade and had been unable to walk by herself due to weakness of the legs since she was 40-years old. At that time, she was diagnosed with diabetes mellitus (DM). She also had difficulty breathing when she was in a supine position. On admission, sural nerve biopsy showed a marked decrease of large and small myelinated fibers and numerous onion bulb formations, which are compatible with CMT type 1. Chest X-ray showed bilateral elevation of the diaphragm, which was more marked on the right side, indicating bilateral PNP. Since it is reported that CMT patients show demyelination of the phrenic nerve subclinically, and DM itself may facilitate the development of PNP, periodic evaluations of respiratory function may thus be useful for preventing respiratory failure in patients with CMT, especially when it is complicated with DM.

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DOI： 10.1034/j.1600-0404.2002.1o028.x

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 59-year-old man, who was diagnosed as having Parkinson's disease and depression seven years ago and was on oral antiparkinsonian agents, antianxiety agents, and antidepressants, developed a high fever, disturbed consciousness, and marked muscle rigidity after discontinuation of etizolam and amitriptyline. He was admitted to a nearby hospital. Hypothyroidism had been noted two months before admission. Marked muscle rigidity and increased serum CK were observed. Since discontinuation of benzodiazepine has been known to rarely trigger a neuroleptic malignant syndrome (NMS), he was diagnosed as having NMS. After receiving dantrolene and bromocriptine, these symptoms temporarily improved but he again developed consciousness disturbance, and convulsive seizures associated with an elevated serum CK. He was transferred to our hospital. On admission, the CK level was normal at 168 IU/l, while free T4 was 0.6 ng/dl (normal range, 0.9-2.3) and TSH was 108.7 mU/ml (normal range, 0.2-4.2) in serum, indicating the presence of primary hypothyroidism. As an increase in thyroid hormone dosage improved the thyroid function to normal level, his disturbed consciousness and muscle rigidity gradually improved. Convulsive seizure and recurrence of NMS in a short interval are unusual in neuroleptic malignant syndrome. In this patient, hypothyroidism may have contributed to the development of malignant syndrome through metabolic changes of the central dopaminergic system, and discontinuation of etizolam, a kind of benzodiazepine, may have triggered NMS, since there has not been reported that discontinuation of antidepressants including amitriptyline triggers NMS.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Our aim was to localize the generator site of parasagittal epileptiform discharges in a patient with epilepsia partialis continua (EPC) in the right leg. We examined a 32-year-old woman with EPC whose conventional EEG did not show any epileptic discharge. We performed the jerk-locked back averaging (JLA) of EEG and magnetoencephalography (MEG) to localize the dipole source of sharp transients. The myoclonic discharges in the right soleus muscle were used as a trigger pulse. JLA revealed consistent EEG and MEG sharp transients that coincided consistently and constantly preceded the myoclonic jerks. JLA of EEG demonstrated sharp waves paradoxically distributed over the vertex and right hemisphere. However, the estimated dipoles of MEG were localized in a restricted area in the primary leg motor area in the left hemisphere, which was closely located in the abnormal lesion on the brain MRI. JLA of MEG is considered to be a useful non-invasive method for localizing the epileptogenic area in EPC even when paradoxical lateralization of electroencephalographic discharges was noted.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 43-year-old man was admitted to our hospital due to unstable walking, head tilting to the left and difficulty in extending his arm. He was quite healthy until the age of 20 years, when these symptoms appeared and progressed slowly afterward. Due to his unstable walking, he started to use a wheelchair when he was 39 years old. He had no family history of similar disease. On admission, neurological examination revealed spasmodic torticollis, ataxic speech and marked limb and truncal ataxia. Myoclonic jerky flexion of the forearm was induced when he raised and extended his forearm. He also showed mild hyperreflexia in the lower limbs without pathological reflexes. He had weakness and atrophy of the left supraspinatus, infraspinatus, deltoid and biceps brachii muscles and mild superficial sensory impairment in the left axillary nerve territory due to cervical spondylotic radiculopathy of the left C5 root. MRI of the brain demonstrated severe bilateral atrophy of the cerebellar hemispheres and vermis but minimal atrophy of the cerebrum and brainstem. Because surface electromyography revealed continuous discharge with phasic components in the biceps and wrist flexor muscles on extending the upper limbs, the jerky flexion movement of the forearm was considered to be primarily dystonia. Although no giant SEP was observed, a C-response was detected in the long-loop reflex in response to right median nerve stimulation. Nuclear examinations showed diffuse hypoperfusion and decreased glucose metabolism in the cerebellum. Based on these findings, we hypothesized that cerebellar dysfunction may have induced severe dystonic movement resembling myoclonus. We would like to name this complicated involuntary movement an "arm thrust". This is the first case to be reported of sporadic, chronic, progressive cerebellar ataxia accompanied by severe dystonic movement, especially on stretching the forearms, that mimics myoclonic movement.

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DOI： 10.1034/j.1600-0404.2001.00051.x

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DOI： 10.1016/S0165-5728(01)00393-9

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記述言語：日本語   出版者・発行元：日本神経学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2002170768

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記述言語：日本語   出版者・発行元：日本神経学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2002110766

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記述言語：日本語   出版者・発行元：日本神経学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2001266380

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DOI： 10.1016/S0022-510X(00)00481-0

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記述言語：日本語  

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DOI： 10.1023/A:1005634130286

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DOI： 10.1016/S0022-510X(00)00322-1

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記述言語：日本語  

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DOI： 10.1136/jnnp.68.5.665

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記述言語：日本語  

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記述言語：英語   出版者・発行元：The Japanese Society of Internal Medicine  

<i>Objective</i> To clarify the clinical features of MS patients with hyperprolactinemia.<br> <i>Subjects and Methods</i> The serum prolactin level was measured in 67 Japanese patients (19 men and 48 women) with multiple sclerosis (MS) and in 16 patients (4 men and 12 women) with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) using a two-site immunoradiometric assay.<br> <i>Results</i> In the MS patients, 32 were classified as having Asian type MS showing a selective involvement of the optic nerves and spinal cord, while the other 35 were classified as having Western type MS which displayed disseminated central nervous system involvement. In women, the serum prolactin level was found to be significantly higher only in Asian type MS (mean=23.1 ng/ml, n=25) than in HAM/TSP (mean=6.9 ng/ml, n=12) (p=0.0297), while it did not differ significantly in men among the three groups. Hyperprolactinemia was significantly associated with acute relapse involving the optic nerves. All MS patients with hyperprolactinemia (7 women with Asian type MS and 2 women with Western type MS) showed recurrent opticomyelitis either throughout or in the early course of the disease, and also had a higher age of onset, a higher Expanded Disability Status Scale score, a greater visual impairment, and higher cell counts and protein contents in the cerebrospinal fluid than did the normoprolactinemic patients.<br> <i>Conclusion</i> Hyperprolactinemia may be one of the characteristic features of Asian patients with MS who preferentially show the optic nerve involvement.<br>(Internal Medicine 39: 296-299, 2000)

DOI： 10.2169/internalmedicine.39.296

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その他リンク： https://jlc.jst.go.jp/DN/JALC/00088395784?from=CiNii

記述言語：日本語  

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DOI： 10.1016/S0022-510X(99)00309-3

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DOI： 10.1097/00001756-200001170-00033

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DOI： 10.1016/S0022-510X(99)00256-7

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DOI： 10.1093/brain/122.9.1689

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DOI： 10.1016/S0022-510X(99)00098-2

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DOI： 10.1016/S0022-510X(99)00115-X

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DOI： 10.1023/A:1021008626887

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A quantitative method for detection of amyloid β peptides using immunoprecipitation-HPLC-mass spectrometry (IP-LC-MS) is described. Comparison of IP-LC-MS with sandwich ELISA revealed comparable results in the analysis of Aβ 1-40 and Aβ 1-42 derived from fetal guinea pig cell media and cell lysates. The use of IP-LC-MS not only allows a quantitative method for Aβ 1-40 and Aβ 1-42 peptides present in Alzheimer's disease (AD), but allows detection of other Aβ peptide species that may also play a role in the onset of AD in humans.

DOI： 10.1016/S0014-5793(98)00706-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We analyzed the effect of several growth factors and cytokines on the expression of amyloid β protein precursor (APP) mRNAs in cultured mouse neuronal and glial cells. In neuronal cultures from embryonic day-15 brain, Northern blotting revealed that APP mRNAs increased by 1.3 to 2.6-fold when treated with nerve growth factor, basic fibroblast growth factor, interleukin 1, interleukin 2, interleukin 3, interleukin 6 or granulocyte-macrophage colony-stimulating factor but not with tumor necrosis factor α. An S1 nuclease protection assay revealed that the enhanced APP mRNA in neuronal cultures was exclusively APP695 mRNA. On the other hand, astrocyte-enriched cultures prepared from postnatal day-2 brain did not show any significant alteration among these factors. We conclude that certain growth factors and cytokines could enhance APP 695 mRNA expression in neurons in vitro. © 1993.

DOI： 10.1016/0169-328X(93)90181-N

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The expression of 3 beta-amyloid protein precursor (APP) mRNAs (695, 751, and 770) in the cerebral cortex in Alzheimer's disease and other neurodegenerative diseases was analyzed by the S1 nuclease protection assay. We found no significant Alzheimer's disease-specific alteration of APP mRNA expression when compared to the other neurological diseases as controls. Since the expression of this mRNA was not correlated with amyloid deposition, it is possible that gliosis/neuronal loss may secondarily alter APP mRNA expression. However, the current study revealed no significant correlation between them.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

S1 nuclease analysis was used to determine the levels and patterns of three beta amyloid protein precursor (BPP) mRNAs in mouse developmental brain and in primary neuronal and glial cultures. BPP695 mRNA lacking the Kunitz proteinase inhibitor (KPI) domain was detected exclusively in neuronal cultures and increased considerably in late embryonic and early postnatal periods. On the other hand, BPP751 and 770 mRNAs with KPI domain were detected predominantly in astrocyte- and microglia-enriched cultures and increased slightly only in embryonic stages. These results suggest that the product of each BPP mRNA may play a different role in the brain. © 1990.

DOI： 10.1016/0006-291X(90)91729-C

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：大道学館出版部  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01556&link_issn=&doc_id=20190509390006&doc_link_id=%2Fam3daidc%2F2019%2F009604%2F006%2F0424-0426%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fam3daidc%2F2019%2F009604%2F006%2F0424-0426%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01159&link_issn=&doc_id=20190318060014&doc_link_id=10.2169%2Fnaika.108.475&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.108.475&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

試験飴は、砂糖、水飴、香料に1粒あたりクロモジエキスを配合し作製した。プラセボ飴は試験飴からクロモジエキスを除き、カラメルを配合し試験飴と同色に着色したものとした。インフルエンザの予防接種を受けた看護スタッフ135名を対象とし、無作為に試験飴摂取群67名(男性3名、平均37.9±11.9歳)、プラセボ飴摂取群67名(男性6名、平均37.4±10.0歳)に割り付けた。試験食品が起因する有害事象は認めなかった。インフルエンザ罹患者数は試験飴摂取群2名(3.0%)、プラセボ飴摂取群9名(13.4%)で、2群間に有意差を認めた。試験飴摂取群で罹患した2名はいずれもインフルエンザB型で、プラセボ飴摂取群では9名中A型が6名、B型は3名であった。罹患患者のうち複数回インフルエンザに罹患した者はなく、欠勤期間は試験飴摂取群4〜5日、プラセボ飴摂取群2〜6日で違いはみられなかった。インフルエンザに起因しない風邪症状においては、発熱、のど、鼻に症状が1回以上みられた人数、発症期間、発熱の有無、のど症状の有無、鼻症状の有無についてはいずれも群間に差は認めなかった。

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