Ryozo Kuwano

Publications (50)239.12 Total impact

• Article: SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease.

  Yanan Wen, Akinori Miyashita, Nobutaka Kitamura, Tamao Tsukie, Yuko Saito, Hiroyuki Hatsuta, Shigeo Murayama, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyasu Akatsu, Takayuki Yamamoto, Kenji Kosaka, Haruyasu Yamaguchi, Kohei Akazawa, Yasuo Ihara, Ryozo Kuwano
  [show abstract] [hide abstract]
  ABSTRACT: SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.
  Journal of Alzheimer's disease: JAD 03/2013; · 3.74 Impact Factor
• Source

  Available from: Hong-Hee Won

  Article: SORL1 Is Genetically Associated with Late-Onset Alzheimer's Disease in Japanese, Koreans and Caucasians.

  Akinori Miyashita, Asako Koike, Gyungah Jun, Li-San Wang, Satoshi Takahashi, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Hiroyuki Arai, [......], Makiko Yoshida, Nao Nishida, Katsushi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard D Schellenberg, Lindsay A Farrer, Ryozo Kuwano
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  ABSTRACT: To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
  PLoS ONE 01/2013; 8(4):e58618. · 4.09 Impact Factor
• Article: A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease

  Tsuyoshi Hamaguchi, Akiyoshi Morinaga, Tamao Tsukie, Ryozo Kuwano, Masahito Yamada
  Journal of Neurology 04/2012; 256(9):1575-1577. · 3.47 Impact Factor
• Article: Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease.

  Nobuto Kakuda, Mikio Shoji, Hiroyuki Arai, Katsutoshi Furukawa, Takeshi Ikeuchi, Kohei Akazawa, Mako Takami, Hiroyuki Hatsuta, Shigeo Murayama, Yasuhiro Hashimoto, Masakazu Miyajima, Hajime Arai, Yu Nagashima, Haruyasu Yamaguchi, Ryozo Kuwano, Kazuhiro Nagaike, Yasuo Ihara
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  ABSTRACT: We investigated why the cerebrospinal fluid (CSF) concentrations of Aβ42 are lower in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Because Aβ38/42 and Aβ40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain γ-secretase activity, and were quantified by specific enzyme-linked immunosorbent assays in the CSF from controls and MCI/AD patients. Decreases in the levels of the precursors, Aβ42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, Aβ38 and 40, respectively. The ratios Aβ40/43 versus Aβ38/42 in CSF (each representing cleavage efficiency of Aβ43 or Aβ42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that γ-secretase activity in MCI/AD patients is enhanced at the conversion of Aβ43 and 42 to Aβ40 and 38, respectively. Consequently, we measured the in vitro activity of raft-associated γ-secretase isolated from control as well as MCI/AD brains and found the same, significant alterations in the γ-secretase activity in MCI/AD brains.
  EMBO Molecular Medicine 02/2012; 4(4):344-52. · 10.33 Impact Factor
• Article: Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS.

  Atsushi Shiga, Tomohiko Ishihara, Akinori Miyashita, Misaki Kuwabara, Taisuke Kato, Norihiro Watanabe, Akie Yamahira, Chigusa Kondo, Akio Yokoseki, Masuhiro Takahashi, Ryozo Kuwano, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.
  PLoS ONE 01/2012; 7(8):e43120. · 4.09 Impact Factor
• Article: A genome-wide CNV association study on panic disorder in a Japanese population.

  Yoshiya Kawamura, Takeshi Otowa, Asako Koike, Nagisa Sugaya, Eiji Yoshida, Shin Yasuda, Ken Inoue, Kunio Takei, Yoshiaki Konishi, Hisashi Tanii, [......], Mamoru Tochigi, Chihiro Kakiuchi, Tadashi Umekage, Xiaoxi Liu, Nao Nishida, Katsushi Tokunaga, Ryozo Kuwano, Yuji Okazaki, Hisanobu Kaiya, Tsukasa Sasaki
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  ABSTRACT: Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in ≥5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features.
  Journal of Human Genetics 12/2011; 56(12):852-6. · 2.57 Impact Factor
• Article: [Laboratory diagnosis and biomarkers of Alzheimer's disease].

  Ryozo Kuwano, Akinori Miyashita, Tamao Tsukie
  Nippon rinsho. Japanese journal of clinical medicine 10/2011; 69 Suppl 8:476-83.
• Article: [Genetic diagnosis and imaging genetics of Alzheimer's disease].

  Akinori Miyashita, Ryozo Kuwano
  Nippon rinsho. Japanese journal of clinical medicine 10/2011; 69 Suppl 8:565-9.
• Article: [Apolipoprotein E gene].

  Ryozo Kuwano, Akinori Miyashita
  Nippon rinsho. Japanese journal of clinical medicine 10/2011; 69 Suppl 8:93-7.
• Source

  Available from: Morihiro Sugishita

  Article: Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation.

  Takeshi Ikeuchi, Toru Imamura, Yasuhiro Kawase, Yoshimi Kitade, Miyuki Tsuchiya, Takayoshi Tokutake, Kensaku Kasuga, Ryuji Yajima, Tamao Tsukie, Akinori Miyashita, Morihiro Sugishita, Ryozo Kuwano, Masatoyo Nishizawa
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  ABSTRACT: Mutations in MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Patients with the MAPT R406W mutation were reported to show phenotypic heterogeneity in different ethnic backgrounds. We here report the clinical and genetic characteristics of Japanese families with the R406W mutation. We examined the clinical and neuroimaging features of 6 patients from three families with the R406W mutation. We determined the genotypes of intragenic MAPT single-nucleotide polymorphisms (SNPs) and the flanking microsatellite markers to search for a common founder. The initial symptom was memory loss with the average age at onset being 54 years. Anterograde amnesia with episodic memory impairment was the predominant phenotype. Behavioral and personality changes or parkinsonism is not a prominent feature. A brain MRI study revealed marked atrophy of the medial temporal lobe. Genetic analysis of SNPs and microsatellite markers revealed that the affected members of the three families share common genotypes. The findings of the affected members in this study, which corroborate previously reported findings of European families, suggest that the R406W mutation may represent a phenotype of predominant anterograde amnesia in FTLD-17. Our genetic data suggest that a founder effect may account for some families with the R406W mutation.
  Dementia and geriatric cognitive disorders extra. 01/2011; 1(1):267-75.
• Source

  Available from: Atsushi Tajima

  Article: Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population.

  Sosuke Adachi, Atsushi Tajima, Jinhua Quan, Kazufumi Haino, Kosuke Yoshihara, Hideaki Masuzaki, Hidetaka Katabuchi, Kenichiro Ikuma, Hiroshi Suginami, Nao Nishida, Ryozo Kuwano, Yuji Okazaki, Yoshiya Kawamura, Tsukasa Sasaki, Katsushi Tokunaga, Ituro Inoue, Kenichi Tanaka
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  ABSTRACT: To identify susceptibility genes for endometriosis in Japanese women, genome-wide association (GWA) analysis was performed using two case-control cohorts genotyped with the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. In each of the two array cohorts, stringent quality control (QC) filters were applied to newly obtained genotype data, together with previously analyzed data from the Japanese Integrated Database Project. After QC-based filtering of samples and single nucleotide polymorphisms (SNPs) in each cohort, 282 838 SNPs in both genotyping platforms were tested for association with endometriosis using a meta-analysis of the two GWA studies with 696 patients with endometriosis and 825 controls. The meta-analysis revealed that a common susceptibility locus conferring a large effect on the disease risk was unlikely. On the other hand, an excess of SNPs with P-values <10(-4) (36 vs 28 SNPs expected by chance) was observed in the meta-analysis. Of note, four of the top five SNPs with P-values <10(-5) were located in and around IL1A (interleukin 1α), which might be a functional candidate gene for endometriosis. Further studies with larger case-control cohorts will be necessary to elucidate the genetic risk factors.
  Journal of Human Genetics 12/2010; 55(12):816-21. · 2.57 Impact Factor
• Source

  Available from: Osamu Onodera

  Article: Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

  Nadezda Maksimova, Kenju Hara, Irina Nikolaeva, Tan Chun-Feng, Tomoaki Usui, Mineo Takagi, Yasushi Nishihira, Akinori Miyashita, Hiroshi Fujiwara, Tokuhide Oyama, Anna Nogovicina, Aitalina Sukhomyasova, Svetlana Potapova, Ryozo Kuwano, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera
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  ABSTRACT: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. To identify a causative gene for SOPH syndrome. Genomewide homozygosity mapping was conducted in 33 patients in 30 families. The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.
  Journal of Medical Genetics 08/2010; 47(8):538-48. · 6.36 Impact Factor
• Article: Neuropathological asymmetry in argyrophilic grain disease.

  Tadashi Adachi, Yuko Saito, Hiroyuki Hatsuta, Sayaka Funabe, Aya M Tokumaru, Kenji Ishii, Tomio Arai, Motoji Sawabe, Kazutomi Kanemaru, Akinori Miyashita, Ryozo Kuwano, Kenji Nakashima, Shigeo Murayama
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  ABSTRACT: The presence of argyrophilic grains in the neuropil is associated with a form of dementia. We investigated morphological asymmetry in 653 consecutive autopsy patients from a general geriatric hospital (age [mean +/- SD] = 81.1 +/- 8.9 years), focusing on those from patients with advanced argyrophilic grain disease. Paraffin sections of the bilateral posterior hippocampi were immunostained with anti-phosphorylated tau and anti-4-repeat tau antibodies and by the Gallyas-Braak method. In a side-to-side comparison, asymmetry was defined when either the extent or the density of argyrophilic grains was different. Of the 653 subjects, 65 (10%) had Stage 3 argyrophilic grain disease, and 59 (90.8%) showed histopathological asymmetry. Antemortem computed tomographic images (n = 24), magnetic resonance imaging scans (n = 8), and combined computed tomographic and magnetic resonance images (n = 15) were available; images from 20 of the 47 subjects showed asymmetry that correlated with the histopathological asymmetry. Cerebral cortical asymmetry consistent with the histopathology was also visible in N-isopropyl-123I-p-iodoamphetamine single photon emission computed tomographic images from 6 patients and 18F-labeled fluorodeoxyglucose positron emission tomographic images from 2 patients. Thus, asymmetric involvement of the medial temporal lobe in patients with advanced argyrophilic grain disease may represent a diagnostic feature and contribute to distinguishing dementia with grains from Alzheimer disease.
  Journal of Neuropathology and Experimental Neurology 07/2010; 69(7):737-44. · 4.26 Impact Factor
• Article: Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity.

  Yong-Juan Fu, Yasushi Nishihira, Shigetoshi Kuroda, Yasuko Toyoshima, Tomohiko Ishihara, Makoto Shinozaki, Akinori Miyashita, Yue-Shan Piao, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Keisuke Iwanaga, Mitsuhiro Tsujihata, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa, Akiyoshi Kakita, Takeshi Ikeuchi, Hitoshi Takahashi
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  ABSTRACT: Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.
  Acta Neuropathologica 02/2010; 120(1):21-32. · 9.32 Impact Factor
• Source

  Available from: PubMed Central

  Article: A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations.

  Kenichiro Yamada, Kiyokuni Miura, Kenju Hara, Motomasa Suzuki, Keiko Nakanishi, Toshiyuki Kumagai, Naoko Ishihara, Yasukazu Yamada, Ryozo Kuwano, Shoji Tsuji, Nobuaki Wakamatsu
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  ABSTRACT: SLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernicke's-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases. We conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions. Genome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient. Our cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.
  BMC Medical Genetics 01/2010; 11:171. · 2.33 Impact Factor
• Article: Genetic deficiency of plasma lipoprotein-associated phospholipase A2 (PLA2G7 V297F null mutation) and risk of Alzheimer's disease in Japan.

  Beena Koshy, Akinori Miyashita, Pamela St Jean, Heide Stirnadel, Toshihiko Kaise, Justin P Rubio, Vincent Mooser, Ryozo Kuwano, Michael C Irizarry
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  ABSTRACT: High plasma lipoprotein phospholipase A2 activity (Lp-PLA2) is reported to be a risk factor for dementia. A loss of function polymorphism in the Lp-PLA2 gene - PLA2G7 V279F - is found almost exclusively in Asians. In 1,952 subjects with late-onset AD and 2,079 non-demented controls recruited from Japan, the PLA2G7 null allele was not associated with risk or age at onset of AD: logistic regression OR 0.98 (95% CI 0.86-1.12, p=0.81) per additional null allele, adjusted for age/age at onset, gender, and APOE ε4. Genetic deficiency of Lp-PLA2 activity is not associated with a reduced risk of AD in the Japanese population.
  Journal of Alzheimer's disease: JAD 01/2010; 21(3):775-80. · 3.74 Impact Factor
• Article: The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system.

  Kanta Yanagida, Masayasu Okochi, Shinji Tagami, Taisuke Nakayama, Takashi S Kodama, Kouhei Nishitomi, Jingwei Jiang, Kohji Mori, Shin-Ichi Tatsumi, Tetsuaki Arai, [......], Toshihisa Tanaka, Takashi Morihara, Ryota Hashimoto, Takashi Kudo, Harald Steiner, Christian Haass, Kuniaki Tsuchiya, Haruhiko Akiyama, Ryozo Kuwano, Masatoshi Takeda
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  ABSTRACT: Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-beta (Abeta42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived Abeta-like peptides (APL1beta) that are generated by beta- and gamma-cleavages at a concentration of approximately 4.5 nM. These novel peptides, APL1beta25, APL1beta27 and APL1beta28, were not deposited in AD brains. Interestingly, most gamma-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Abeta42 cause a parallel increase in the production of APL1beta28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1beta28 levels are higher than in non-AD controls, while the relative Abeta42 levels are unchanged or lower. Most strikingly, the relative APL1beta28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1beta28 in the CSF as a candidate surrogate marker for the relative level of Abeta42 production in the brain.
  EMBO Molecular Medicine 07/2009; 1(4):223-35. · 10.33 Impact Factor
• Article: [Genetic basis for dementia].

  Ryozo Kuwano, Norihiro Takei, Akinori Miyashita
  [show abstract] [hide abstract]
  ABSTRACT: A goal of genetic research is to identify risk factor loci for complex disorders, and to understand a molecular mechanism of the factor on development of the disease. Dementia is the most common neurodegererative disorder in the elderly. Three frequent neurodegererative dementias are Alzheimer disease, dementia with Lewy bodies, and frontotemporal lobar degeneration, characterized by senile plaque with amyloid beta and neurofibrillary tangles with tau, Lewy body with alpha-synuclein, tau or tau-negative ubiquitin-immunoreactive neuronal inclusions with TDP-43, respectively. Overlapping symptoms, progress and neuropathological findings often complicate the diagnosis. Genetic risk factors obtained by genome-wide association study might provide new insight into etiology common to dementia.
  Nippon rinsho. Japanese journal of clinical medicine 07/2009; 67(6):1078-82.
• Article: A novel presenilin 1 mutation (L282F) in familial Alzheimer's disease.

  Tsuyoshi Hamaguchi, Akiyoshi Morinaga, Tamao Tsukie, Ryozo Kuwano, Masahito Yamada
  Journal of Neurology 06/2009; 256(9):1575-7. · 3.47 Impact Factor
• Article: Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese.

  Norihiro Takei, Akinori Miyashita, Tamao Tsukie, Hiroyuki Arai, Takashi Asada, Masaki Imagawa, Mikio Shoji, Susumu Higuchi, Katsuya Urakami, Hideo Kimura, Akiyoshi Kakita, Hitoshi Takahashi, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Shoji Odani, Ryozo Kuwano
  [show abstract] [hide abstract]
  ABSTRACT: The epsilon4 allele of APOE is a well-characterized genetic risk factor for late-onset Alzheimer disease (LOAD). Nevertheless, using high-density single nucleotide polymorphisms (SNPs), there have only been a few studies involving genetic association and linkage disequilibrium (LD) analyses of in and around the APOE. Here, we report fine mapping of a genomic region (about 200 kb) including the APOE in Japanese using 260 SNPs (mean intermaker distance, 0.77 kb). A case-control study demonstrated that 36 of these SNPs exhibited significance after adjustment for multiple testing. These SNPs are located in a genomic region including four genes, PVRL2, TOMM40, APOE and APOC1. Recombination rate estimation revealed that the associated region is firmly sandwiched between two recombination hotspots. Strong LD between these SNPs was observed (mean |D'|=0.914). These data suggest that the three genes other than APOE, i.e. PVRL2, TOMM40 and APOC1, could also yield a predisposition to LOAD.
  Genomics 06/2009; 93(5):441-8. · 3.02 Impact Factor