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Naohiro Egawa,
Shiho Kitaoka,
Kayoko Tsukita,
Motoko Naitoh,
Kazutoshi Takahashi,
Takuya Yamamoto,
Fumihiko Adachi,
Takayuki Kondo,
Keisuke Okita,
Isao Asaka, [......],
Takashi Nonaka,
Masato Hasegawa,
Akihiro Kawata,
Minoru Yoshida,
Tatsutoshi Nakahata,
Ryosuke Takahashi,
Maria C N Marchetto,
Fred H Gage,
Shinya Yamanaka,
Haruhisa Inoue
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ABSTRACT: Our work and the study of Bilican et al. highlight the need for complementary assays to detect subtle phenotypic differences between control and mutant induced pluripotent stem cell lines.
Science translational medicine 06/2013; 5(188):188lr2. · 7.80 Impact Factor
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ABSTRACT: It has been reported that abnormal processing of pre-mRNA is caused by abnormal triplet expansion. Non-coding triplet expansions produce toxic RNA to alter RNA splicing activities. However, there has been no report on the globular RNA aggregation in neuronal cytoplasmic inclusions (NCIs) up to now. We herein report on an autopsy case (genetically determined as spinocerebellar atrophy 8 (SCA8)) with hitherto undescribed NCIs throughout the brain. NCIs were chiefly composed of small granular particles, virtually identical to ribosomes. Neurological features are comparable to the widespread lesions of the brain, including the spinal cord. Although 1C2-positivity of NCIs might be induced by reverse transcription of the CTG expansion, it remains to be clarified how abnormal aggregations of ribosome and extensive brain degeneration are related to the reverse or forward transcripts of the expanded repeat.
Neuropathology 05/2013; · 2.02 Impact Factor
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ABSTRACT: Grover's disease is an acquired dermatosis of unknown cause histopathologically characterized by the presence of acantholysis. We report an 83-year-old Japanese man who showed multiple pruritic papular lesions distributed bilaterally along Blaschko lines, necessitating the exclusion of segmental Darier's disease. No mutations in ATP2A2, ATP2C1 or keratin 5 genes were found both in the lesional skin and in peripheral leukocytes, suggesting that putative pathogenesis of Grover's disease is distinct from those of other acantholytic dermatoses. Electron microscopy revealed poorly developed tonofibrils in the basal cells, and the structure of desmosomes appeared normal, with an increase in the number of desmosomes in the spinous layer, indicating compensation of defective desmosomal function. Impairment of desmosomal plaque proteins linking tonofilaments to desmosomal cadherins may thus account for acantholysis. The unusual bilateral mosaic arrangement in our patient may offer valuable clues to the genetic basis of Grover's disease.
Dermatology 10/2012; · 2.05 Impact Factor
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Yoshikuni Mizuno,
Mitsutoshi Yamamoto,
Sadako Kuno, Kazuko Hasegawa,
Nobutaka Hattori,
Tatsuro Kagimura,
Akiko Sarashina,
Olivier Rascol,
Anthony H V Schapira,
Paolo Barone,
Robert A Hauser,
Werner Poewe
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ABSTRACT: To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD).
After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase.
Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER.
In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.
Clinical neuropharmacology 07/2012; 35(4):174-81. · 2.35 Impact Factor
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Ikuko Mizuta,
Tatsuhiko Tsunoda,
Wataru Satake,
Yuko Nakabayashi,
Masahiko Watanabe,
Atsushi Takeda, Kazuko Hasegawa,
Kenji Nakashima,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Tatsushi Toda
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ABSTRACT: Parkinson’s disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic
neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes
identified α-synuclein (SNCA) as a susceptibility gene for sporadic PD (P=1.7×10−11). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P=0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes,
but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P<0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent
sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P=7.1×10−5; recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of
CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests
that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA.
Human Genetics 04/2012; 124(1):89-94. · 5.07 Impact Factor
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Sachiko Ujiie,
Taku Hatano,
Shin-Ichiro Kubo,
Satoshi Imai,
Shigeto Sato,
Toshiki Uchihara,
Saburo Yagishita, Kazuko Hasegawa,
Hisayuki Kowa,
Fumihiko Sakai,
Nobutaka Hattori
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ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal-dominant familial Parkinson's disease (FPD). The variable pathological features of LRRK2-linked FPD include Lewy bodies, degeneration of anterior horn cells associated with axonal spheroids, neurofibrillary tangles (NFTs) and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusion bodies. Furthermore, abnormal hyperphosphorylation of microtubule associated protein tau, in part generated by catalysis of protein kinases, has been reported to be involved in progressive neurodegeneration in a number of diseases, including FPD. Thus, we examined six patients carrying the LRRK2 I2020T mutation, a pathogenic mutation associated with PARK8, and found abnormal tau phosphorylation depositions in the brainstem. Additionally, we found LRRK2 I2020T enhanced tau phosphorylation in cultured cells co-expressing LRRK2-I2020T and 3 or 4-repeated tau. This is the first report describing the relationship between hyperphosphorylation of tau and LRRK2 I2020T.
Parkinsonism & Related Disorders 04/2012; 18(7):819-23. · 3.80 Impact Factor
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Min Shi,
Amy R Furay,
Vesna Sossi,
Jan O Aasly,
Jeff Armaly,
Yu Wang,
Zbigniew K Wszolek,
Ryan J Uitti, Kazuko Hasegawa,
Teruo Yokoyama,
Cyrus P Zabetian,
James B Leverenz,
A Jon Stoessl,
Jing Zhang
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ABSTRACT: Previous studies demonstrated decreased levels of DJ-1 and α-synuclein (αSYN) in human cerebrospinal fluid (CSF) in patients with Parkinson's disease (PD), but neither marker correlated with PD severity, raising the possibility that they may be excellent progression markers during early or preclinical phases of PD. Individuals carrying the leucine-rich repeat kinase 2 (LRRK2) gene mutation are at increased risk for PD, and the phenotype of LRRK2 patients is almost identical to sporadic PD. To determine whether dopaminergic dysfunction in the basal ganglia, as determined by positron emission tomography (PET) scans, correlates with CSF levels of DJ-1 and αSYN during preclinical stages, Luminex assays were used to analyze CSF samples from asymptomatic LRRK2 mutation carriers, along with carriers who presented with a clinical diagnosis of PD. The data revealed no statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and αSYN, except for a weak correlation between DJ-1 and methylphenidate binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate.
Neurobiology of aging 04/2012; 33(4):836.e5-7. · 5.94 Impact Factor
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ABSTRACT: Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD.
PLoS ONE 01/2012; 7(2):e30958. · 4.09 Impact Factor
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Aritoshi Iida,
Atsushi Takahashi,
Michiaki Kubo,
Susumu Saito,
Naoya Hosono,
Yozo Ohnishi,
Kazuma Kiyotani,
Taisei Mushiroda,
Masahiro Nakajima,
Kouichi Ozaki, [......],
Naoki Atsuta,
Hirohisa Watanabe,
Fumiaki Tanaka,
Ryuji Kaji,
Imaharu Nakano,
Naoyuki Kamatani,
Shoji Tsuji,
Gen Sobue,
Yusuke Nakamura,
Shiro Ikegawa
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 × 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-β (TGF-β) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-β signaling and that decreased ZNF512B expression increases susceptibility to ALS.
Human Molecular Genetics 06/2011; 20(18):3684-92. · 7.64 Impact Factor
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ABSTRACT: PARK8 is the most common form of familial Parkinson's disease (PD). We measured biopterin and monoamine metabolite levels in the cerebrospinal fluids of 7 PARK8 patients (I2020T mutation in leucine-rich repeat kinase 2), 2 asymptomatic mutation carriers, and 21 sporadic PD patients. The biopterin levels in PARK8 patients were significantly higher than those in sporadic PD patients, although the symptoms were comparable in both groups, suggesting that PARK8 patients exhibit parkinsonian symptoms with higher biopterin levels than sporadic PD patients.
Acta Neurovegetativa 02/2011; 118(6):899-903. · 2.73 Impact Factor
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Acta Dermato-Venereologica 11/2010; 91(2):201-3.
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Masahisa Katsuno,
Haruhiko Banno,
Keisuke Suzuki,
Yu Takeuchi,
Motoshi Kawashima,
Ichiro Yabe,
Hidenao Sasaki,
Masashi Aoki,
Mitsuya Morita,
Imaharu Nakano, [......],
Hiroaki Miyajima,
Fumio Kanda,
Yasuhiro Watanabe,
Kenji Nakashima,
Akira Tsujino,
Taro Yamashita,
Makoto Uchino,
Yasushi Fujimoto,
Fumiaki Tanaka,
Gen Sobue
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ABSTRACT: Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy.
The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465.
204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727).
48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients.
Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.
The Lancet Neurology 09/2010; 9(9):875-84. · 23.46 Impact Factor
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ABSTRACT: The objectives of this study were to evaluate the efficacy of istradefylline at an oral dose of 20 mg or 40 mg once daily for 12 weeks in Parkinson's disease (PD) patients with motor complications on levodopa therapy based on the change in the daily OFF time compared with placebo and to assess the safety at these doses. A total of 363 subjects were randomly assigned to receive 20 mg/day istradefylline (n = 119), 40 mg/day istradefylline (n = 125), or placebo (n = 119). The primary outcome variable was the change from baseline at endpoint in daily OFF time based on patients' ON/OFF diaries. At endpoint, the daily OFF time reduced from baseline by 1.31 hours for 20 mg/day istradefylline (P = 0.013 as compared to the placebo), 1.58 hours for 40 mg/day istradefylline (P < 0.001), and 0.66 hours for placebo; istradefylline significantly reduced the daily OFF time compared with placebo. The UPDRS Part III subscale score (ON state) reduced by 5.7 at endpoint in both istradefylline groups and 3.7 in the placebo group (P = 0.006 for 20 mg/day and P = 0.006 for 40 mg/day group as compared with placebo). The most commonly reported drug-related treatment emergent adverse event (TEAE) was dyskinesia, which occurred in 2.5% (3/119) of subjects receiving placebo, 8.5% (10/118) receiving 20 mg/day istradefylline, and 6.4% (8/125) receiving 40 mg/day istradefylline. We conclude that istradefylline at 20 mg and 40 mg once daily is effective in relieving wearing-off fluctuations of PD patients. In addition, istradefylline was well tolerated at both doses.
Movement Disorders 07/2010; 25(10):1437-43. · 4.51 Impact Factor
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Acta Dermato-Venereologica 07/2010; 90(4):427-8.
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ABSTRACT: Olfactory involvement is well recognized in patients with Parkinson's disease (PD). The purpose of this study was to examine smell function quantitatively, using different types and concentrations of odorants in PD patients. We aimed to elucidate whether a specific odor can affect the severity and duration of PD patients. A total of 89 nondemented PD patients and 20 age-matched controls participated in the study. Quantitative evaluation of smell function was performed using the T and T olfactometer test. This test contains five kinds of odorants at different concentrations. Recognition threshold (RT) scores for all five odorants and for each individual odorant were measured in five groups of PD patients with Hoehn and Yale (HY) stages I (n = 12), II (n = 24), III (n = 43), and IV (n = 10), as well as in control subjects (n = 20). One-way analysis of variance and Ryan's method were used for statistical comparison between the five groups. Compared with controls and HY I patients, total RT scores were significantly higher in HY II, III, and IV patients. There were no statistically significant differences in RT scores between HY I patients and controls. However, total RT scores for three HY I patients (25%) were higher than the mean + two standard deviations of controls. On single odorant testing, significant higher RT scores for methylcyclopentenolone and skatol were found in HY II, III, and IV patients, in comparison with controls and HY I patients. The remaining three odorants did not differ statistically between PD patients and control subjects. The present study indicated that hyposmia in PD patients increased from HY II onwards. A single odorant of methyl cyclopentenolone or skatol had benefits for olfactory evaluation in PD patients. Our data also clarified that olfactory deficits occurred in a subset of HY I patients. Further prospective study is needed to elucidate whether a distinct profile of PD exists between HY I patients with and without hyposmia.
International Journal of General Medicine 01/2010; 3:181-5.
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Wataru Satake,
Yuko Nakabayashi,
Ikuko Mizuta,
Yushi Hirota,
Chiyomi Ito,
Michiaki Kubo,
Takahisa Kawaguchi,
Tatsuhiko Tsunoda,
Masahiko Watanabe,
Atsushi Takeda, [......], Kazuko Hasegawa,
Fumiya Obata,
Takeo Yoshikawa,
Hideshi Kawakami,
Saburo Sakoda,
Mitsutoshi Yamamoto,
Nobutaka Hattori,
Miho Murata,
Yusuke Nakamura,
Tatsushi Toda
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ABSTRACT: To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.
Nature Genetics 11/2009; 41(12):1303-7. · 35.53 Impact Factor
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ABSTRACT: We report autopsy cases of two siblings who developed muscular atrophy and dementia, clinically considered to be familial motor neuron disease (MND). They presented with motor neuron signs predominantly in the distal limbs without sensory impairment. At autopsy, severe neuronal loss in the anterior horn consistent with MND was found, but histopathological hallmarks like Bunina bodies and skein-like inclusions were absent. Surprisingly, numerous huge axonal swellings (about 30 microm in diameter) and onion-bulb-like structures were found in the spinal ventral roots. These changes were not observed in spinal dorsal roots or peripheral nerves. However, obvious segmental demyelination of the ventral root was not found. In addition, neurofibrillary tangles (NFTs) and neuritic plaques were present in the frontal cortex, temporal cortex and hippocampus, and to a lesser degree, in the amygdala, substantia nigra and thalamus. Our two cases are a hitherto unreported type of MND, which shows focal giant axonopathy and prominent formation of onion-bulb-like structures due to Schwann cell proliferation restricted to the spinal ventral roots.
Neuropathology 07/2009; 30(1):61-70. · 2.02 Impact Factor
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ABSTRACT: Up to now diffuse white matter demyelination of the cerebrum has been reported in only a few cases of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). Here we document an autopsy case with this rare neuropathology. Most MELAS cases are diagnosed antemortem by A3243G transition of mitochondrial DNA. While cerebral damage including necrotic foci in the cerebral cortex are common findings in MELAS, prominent white matter involvement best characterizes this MELAS case. There were numerous necrotic foci, varying in size and chronological stage, in the cerebral white matter. In the areas of the white matter without necrotic foci, there was diffuse fibrillary gliosis with the loss of axons and oligodendrocytes. The gliosis was dominant in the deep white matter, sparing the U-fiber. The cerebral cortex showed diffuse cortical atrophy with few scattered necrotic foci. Distribution of the cerebral lesions does not coincide with the territory of blood supply. The vascular wall presented only slight to mild hyalinosis. We assumed a common pathogenesis to the cortical lesions and the white matter change. The pathogenesis of the present diffuse cerebral lesions may not be just secondary to circulatory disturbance but partly due to metabolic abnormality.
Neuropathology 07/2009; 30(1):56-60. · 2.02 Impact Factor
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ABSTRACT: Parkinson disease (PD) and dystonia are two major part of neurodegenerative disorders. The underlying cause of PD development has been considered to be a combination of genetic factors and environmental substrates. In case of dystonia, which includes primary sporadic dystonia, such as task specific dystonia, cervical dystonia and so on, are also considered to associate with unknown vulnerable genetic factors. In this paper, the clinical features and causative genes for PD and dystonia were described; especially in particular, the description of those genes associated with the PARK and DYT series were provided. Most of the identified causative genes for PD are associated with the protein degradation and cell death process via convergent mechanisms such as ubiquitin-proteasome system, mitochondrial dysfunction, oxidative stress, and lysosomal system (autophagia). On the other hand, the pathogenic mechanism for dystonia is gradually discovered to be divergent suggested by identified genes, such as torsinA, GCH1, etc, which is compatible and well understood with the divergent expression of dystonia phenotype. Another breakthroughs are required to investigate the treatment of both PD and dystonia based on the pathogenic mechanisms.
Brain and nerve = Shinkei kenkyū no shinpo 05/2009; 61(4):447-63.
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ABSTRACT: Insulin-like growth factor-I (IGF-I) is a potent survival factor for motor neurons in animals, and glycogen synthase kinase-3beta (GSK-3beta) is suspected to play roles in apoptosis and tau phosphorylation. Here we report the immunological expression of IGF-I, GSK-3beta, phosphorylated-GSK-3alpha/beta (p-GSK-3alpha/beta) and phosphorylated-tau in the spinal cord and hippocampus of Kii and Guam amyotrophic lateral sclerosis (ALS) patients. Sixteen ALS patients (10 Japanese sporadic, 3 Kii and 3 Guam ALS) and 14 neurological controls (10 Japanese and 4 Guamanian) were examined. The immunoreactivity for each antibody was rated by the percentages of positive neurons to total anterior horn neurons in each patient and was analyzed statistically. Many normal-looking neurons from Japanese sporadic ALS, Kii ALS and Guam ALS patients, as well as from Japanese and Guam controls, were positive for anti-IGF-I antibody. A positive correlation between IR scores for anti-IGF-I antibody and clinical durations of Japanese sporadic ALS patients was found in this study (P < 0.0001). This suggested that IGF-I might have a protective effect against ALS degeneration. In Japanese sporadic ALS patients, abnormal as well as normal-looking neurons showed significant high IR scores for anti-GSK-3beta antibody than those of controls. Anterior horn neurons from Guam and Kii ALS patients characteristically showed weak staining for anti-GSK-3beta antibody but were markedly positive for anti-pGSK-3alpha/beta antibody compared to those from both Japanese controls and Japanese sporadic ALS patients, and showed the co-localization of IGF-I and p-GSK-3alpha/beta. This suggested that the IGF-I signaling pathway in Guam and Kii ALS patients might function to phosphorylate GSK-3beta to protect neurons from ALS degeneration. Neurofibrillary tangles (NFTs) in the hippocampus and spinal cord from Kii and Guam ALS patients showed the co-localization of PHF-tau and p-GSK-3alpha/beta by a confocal laser scanning technique. The predominant expression of p-GSK-3alpha/beta compared to GSK-3beta in spinal motor neurons and the co-localization of p-GSK-3alpha/beta and PHF-tau in NFT-laden neurons in the hippocampus and spinal cord were characteristic findings of Kii and Guam ALS patients.
Neuropathology 04/2009; 29(5):548-58. · 2.02 Impact Factor
