Neuropathology of cognitive decline in Lewy body disease

• Project/Area Number: 20390248
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Metropolitan Institute of Gerontology
• Principal Investigator: MURAYAMA Shigeo Tokyo Metropolitan Institute of Gerontology, 東京都健康長寿医療センター研究所, 研究部長 (50183653)
• Co-Investigator(Kenkyū-buntansha): SAITO Yuko 独立行政法人国立精神・神経医療研究センター, 臨床検査部, 室長 (60344066)
• Co-Investigator(Renkei-kenkyūsha): ISHII Kenji 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 (10231135) ; HATSUTA Hiroyuki 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (60469963)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2010: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2009: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2008: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
• Keywords: αシヌクレイン / タウ / βアミロイド / パーキンソン病 / レビー小体型認知症 / PIB PET / MRI / ドーパミン / アミロイドβ蛋白 / レビー小体 / 老人班 / 神経原線維変化 / 11C-PIB PET / バーチュアルスライド

Research Abstract

We studied to identify anatomic substrates to explain dementia in Lewy body disease. Neuropathologically, consecutive autopsy cases were immunocytochemically studied for difference in Lewy body dementia (dementia with Lewy bodies : DLB and Parkinson disease with dementia) Parkinson disease without dementia. Neuroradiologically, PET scans for dopamine transporter (^<11>C-CFT), glucose metabolism (^<18>F-FDG) and amyloid (^<11>C-PIB) were comparatively examined.
Overall, 99 autopsy cases with diagnosis DLB, PDD or PD were recruited for this study. All the cases were immunocytochemically screened for anti-Abta (11-28), phosphorylated tau (AT8) and phosphorylated alpha-synuclein (psyn#64). From 2008-2010, three more autopsy cases were newly recruited for this study. Substrates of DLB/PDD-PD consisted of neocortical plaque as well as alpha-sunuclein deposition in neocortex, limbic system and caudate nucleus. Substrates of Lewy body dementia with neocortical amyloid positive and negative case s consisted of limbic and necortical alpha-synuclein but not striatal alpha-synuclein. Twenty three cases of pure Lewy body dementia with sufficient alpha-synuclein deposition without significant Abeta and tau deposition were selected from consecutive 8344 autopsy cases and 20 were classified into limbic form and 3 into neocortical form. These pure Lewy body cases lacked striatal Abeta deposition.
About clinical PET studies, three each of DLB/PDD and PD cases were recruited for the study. Decreased ^<11>C-CFT uptake in caudate nucleus of DLB/PDD patients were confirmed. About ^<11>C-PIB PET scans, the three PD cases lacked cortical uptake at all and two out of three PDD/DLB cases also lacked cortical uptake. Thus, the correlation between striatal ^<11>C-CFT uptake and ^<11>C-PIB could not be calculated.
Our data confirmed anatomical substrate for dementia in Lewy body disease consisted of deposition of alpha-synuclein in limbic and neocortical structure. Our study also highlighted deposition of alpha-synuclein in caudate nucleus as strategic target for Lewy body dementia Our study could not confirm the previous reports that striatal deposition of Abeta is responsible for Lewy body dementia.
Pathogenesis of alpha-synuclein deposition and decreased DAT scan in caudate nucleus in Lewy body dementia is yet to be clarified.

Research Products

• [Journal Article] Validation of cardiac 123I-MIBG scintigraphy in patients with Parkinson's disease who were diagnosed with dopamine PET. (2010)
  • Author(s): Ishibashi K, Saito Y, Murayama S, Kanemaru K, Oda M, Ishiwata K, Mizusawa H, Ishii K
  • Journal Title: Eur J Nucl Med Mol Imaging 37 Pages: 3-11
• [Journal Article] Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson's disease. (2010)
  • Author(s): Ishibashi K, Kanemaru K, Saito Y, Murayama S, Oda K, Ishiwata K, Mizusawa H, Ishii K
  • Journal Title: Acta Neurol Scand 122 Pages: 46-50
• [Journal Article] α-Synuclein accumulation in skin nerve fibers revealed by skin biopsy in pure autonomic failure. (2010)
  • Author(s): Shishido T, Ikemura M, Obi T, Yamazaki K, Terada T, Sugiura A, Saito Y, Murayama S, Mizoguchi K
  • Journal Title: Neurology 74 Pages: 608-610
• [Journal Article] Neuropathological asymmetry in argyrophilic grain disease. (2010)
  • Author(s): Adachi T, Saito Y, Hatsuta H, Funabe S, Tokumaru AM, Ishii K, Arai T, Sawabe M, Kanemaru K, Miyashita A, Kusano R, Nakashima K, Murayama S
  • Journal Title: J Neuropath Exp Neurol 69 Pages: 737-744
• [Journal Article] Prospective 10-year surveillance of human prion diseases in Japan Brain (2010)
  • Author(s): Nozaki I, Hamaguchi T, Sanjo N, Noguchi-Shinohara M, Sakai K, Nakamura Y, Sato T, Kitamoto T, Mizusawa H, Moriwaka F, Shiga Y, Kuroiwa Y, Nishizawa M, Kuzuhara S, Inuzuka T, Takeda M, Kuroda S, Abe K, Murai H, Murayama S, Tateishi J, Takumi I, Shirabe S, Harada M, Sadakane A, Yamada M
  • Journal Title: 133 Pages: 3043-3057
• [Journal Article] Protective effect of N-glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer' s disease. (2010)
  • Author(s): Akasaka-Manya K, Manya H, Sakurai Y, Wojczyk B, Kozutsumi, Y, Saito Y, Taniguchi N, Murayama S, Spitalnik S, Endo T
  • Journal Title: Glycosilation Volume: 20 Pages: 99-106
  • Peer Reviewed
• [Journal Article] Validation of cardiac 123I-MIBG scintigraphy inpatients with Parkinson's disease who were diagnosed with dopamine PET. (2010)
  • Author(s): Ishibashi K, Saito Y, Murayama S, Kanemaru K, Oda M, Ishiwata K, Mizusawa H, Ishii K
  • Journal Title: Eur J Nucl Med Mol Imaging Volume: 37 Pages: 3-11
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson's disease. (2010)
  • Author(s): shibashi K, Kanemaru K, Saito Y, Murayama S, Oda K, Ishiwata K, Mizusawa H, Ishii K
  • Journal Title: Acta Neurol Scand Volume: 122 Pages: 46-51
  • Peer Reviewed
• [Journal Article] α-Synuclein accumulation in skin nerve fibers revealed by skin biopsy in pure autonomic failure. (2010)
  • Author(s): Shishido T, Ikemura M, Obi T, Yamazaki K, Terada T, Sugiura A, Saito Y, Murayama S, Mizoguchi K
  • Journal Title: Neurology Volume: 74 Pages: 608-610
  • Peer Reviewed
• [Journal Article] Cortical propagation of creutzfeldt-Jakob disease with codon 180 mutation. (2010)
  • Author(s): Kobayashi S, Saito Y, Maki T, Murayama S
  • Journal Title: Clin Neurol Neurosurg Volume: 112 Pages: 520-523
  • Peer Reviewed
• [Journal Article] Neuropathological asymmetry in argyrophilic grain disease. (2010)
  • Author(s): Adachi T, Saito Y, Hatsuta H, Funabe S, Tokumaru AM, Ishii K, Arai T, Sawabe M, Kanemaru K, Miyashita A, Kusano R, Nakashima K, Murayama S
  • Journal Title: Neuropath Exp Neurol Volume: 69 Pages: 737-744
  • Peer Reviewed
• [Journal Article] Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate. (2010)
  • Author(s): Terada T, Tsuboi Y, Obi T, Doh-ura K, Murayama S, Kitamoto T, Yamada T, Mizoguchi K
  • Journal Title: Acta Neurol Scand Volume: 121 Pages: 127-130
  • Peer Reviewed
• [Journal Article] Prospective 10-year surveillance of human prion diseases in Japan. (2010)
  • Author(s): Nozaki I, Hamaguchi T, Sanjo N, Noguchi-Shinohara M, Sakai K, Nakamura Y, Sato T, Kitamoto T, Mizusawa H, Moriwaka F, Shiga Y, Kuroiwa Y, Nishizawa M, Kuzuhara S, Inuzuka T, Takeda M, Kuroda S, Abe K, Murai H, Murayama S, Tateishi J, Takumi I, Shirabe S, Harada M, Sadakane A, Yamada M
  • Journal Title: Brain Volume: 133 Pages: 3043-3057
  • Peer Reviewed
• [Journal Article] Validation of cardiac 123I-MIBG scintigraphy in patients with Parkinson's disease who were diagnosed with dopamine PET 2009.7.25 Epub (2010)
  • Author(s): Ishibashi K, Saito Y, Murayama S, Kanemaru K, Oda M, Ishiwata K, Mizusawa H, Ishii K
  • Journal Title: Eur J Nucl Med Mol Imaging 37 Pages: 3-11
  • Peer Reviewed
• [Journal Article] Protective effect of N-glycan bisecting GlcNAc residues on □-amyloid production in Alzheimer's disease (2010)
  • Author(s): Akasaka-Manya K, Manya H, Sakurai Y, Wojczyk B, Kozutsumi, Y, Saito Y, Taniguchi N, Murayama S, Spitalnik S, Endo T
  • Journal Title: Glycosilation 20 Pages: 99-106
  • Peer Reviewed
• [Journal Article] Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate (2010)
  • Author(s): Terada T, Tsuboi Y, Obi T, Doh-ura K, Murayama S, Kitamoto T, Yamada T, Mizoguchi K
  • Journal Title: Acta Neurol Scand 121 Pages: 127-130
  • Peer Reviewed
• [Journal Article] Imaging-Pathologic Correlation in Corticobasal Degeneration. (2009)
  • Author(s): Tokumaru A, Saito Y, Murayama S, Kanemaru K, Sakiyama Y, Toyoda M, Yamakawa H, Terada H
  • Journal Title: Am J Neuroradiol 30 Pages: 1884-1892
• [Journal Article] Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)n. (2009)
  • Author(s): Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, Takahashi M, Matsuura T, Flanigan KM, Iwasaki S, Ishino F, Saito Y, Murayama S, Yoshida M, Hashizume Y, Takahashi Y, Tsuji S, Shimizu N, Toda T, Ishikawa K, Mizusawa H
  • Journal Title: Am J Hum Gen 85 (5) Pages: 544-557
• [Journal Article] Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease (2009)
  • Author(s): Fukuda M, Kanou F, Shimada N, Sawabe M, Saito Y, Murayama S, Hashimoto M, Maruyama N, Ishigami A
  • Journal Title: Biomed Res 30 Pages: 227-233
  • NAID: 130004903756
  • Peer Reviewed
• [Journal Article] Imaging-Pathologic Correlation in Corticobasal Degeneration (2009)
  • Author(s): Tokumaru A, Saito Y, Murayama S, Kanemaru K, Sakiyama Y, Toyoda M, Yamakawa H, Terada H
  • Journal Title: Am J Neuroradiol 30 Pages: 1884-1892
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia type 31 is associated with"inserted"penta-nucleotid repeats containing(TGGAA)n (2009)
  • Author(s): Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, Takahashi M, Matsuura T, Flanigan KM, Iwasaki S, Ishino F, Saito Y, Murayama S, Yoshida M, Hashizume Y, Takahashi Y, Tsuji S, Shimizu N, Toda T, Ishikawa K, Mizusawa H
  • Journal Title: Am J Hum Gen 85 Pages: 544-557
  • Peer Reviewed
• [Journal Article] 顕微鏡的多発性血管炎に対してステロイド療法中、原因不明の発熱が出現し、死亡した1例 (2009)
  • Author(s): 杉原毅彦, 木村直樹, 村山繁雄, 新井冨生, 井藤英喜, 稲松孝思, 大田雅嗣, 原田和昌
  • Journal Title: Geriat Med 47 Pages: 387-396
  • Peer Reviewed
• [Journal Article] リハの基礎となる動的神経病理(画像・病理連関). 脳血管障害 (2009)
  • Author(s): 村山繁雄
  • Journal Title: Jounal of Clinical Rehabilitation 18 Pages: 4-8
• [Journal Article] リハの基礎となる動的神経病理(画像・病理連関). 脳血管障害 (2009)
  • Author(s): 村山繁雄、齊藤祐子、徳丸阿耶
  • Journal Title: Jounal of Clinical Rehabilitation 18 Pages: 100-104
• [Journal Article] リハの基礎となる動的神経病理(画像・病理連関). 頭部外傷 (2009)
  • Author(s): 村山繁雄、齊藤祐子、徳丸阿耶
  • Journal Title: Jounal of Clinical Rehabilitation 18 Pages: 192-196
• [Journal Article] リハの基礎となる動的神経病理(画像・病理連関). アルツハイマー病 (2009)
  • Author(s): 村山繁雄、齊藤祐子、徳丸阿耶
  • Journal Title: Jounal of Clinical Rehabilitation 18 Pages: 292-296
• [Journal Article] リハの基礎となる動的神経病理(画像・病理連関). パーキンソン病 (2009)
  • Author(s): 齊藤祐子、足立正、村山繁雄
  • Journal Title: Jounal of Clinical Rehabilitation 18 Pages: 392-396
• [Journal Article] MCIを考える。高齢者ブレインバンクプロジェクトの経験から (2009)
  • Author(s): 村山繁雄
  • Journal Title: 神経心理学 29 Pages: 35-40
• [Journal Article] 大脳白質の機能解剖学 (2009)
  • Author(s): 村山繁雄、齊藤祐子
  • Journal Title: 分子脳血管病 8 Pages: 131-135
• [Journal Article] 異常タンパク蓄積と神経変性、アルツハイマー病を中心に (2009)
  • Author(s): 村山繁雄、齊藤祐子
  • Journal Title: 実験医学 27 Pages: 1356-1360
• [Journal Article] Basophilic inclusion body disease and neuronal intermediate filament inclusion disease : a comparative clinicopathological study. (2008)
  • Author(s): Yokota O, Tsuchiya K, Terada S, Ishizu H, Uchikado H, Ikeda M, Oyanagi K, Nakano I, Murayama S, Kuroda S, Akiyama H
  • Journal Title: Acta Neuropath 115 Pages: 561-575
• [Journal Article] Presynaptic and postsynaptic nigrostriatal dopaminergic functions in multiple system atrophy. (2008)
  • Author(s): Hashimoto M, Kawasaki K, Suzuki M, Mitani K, Murayama S, Mishina M, Oda K, Kimura Y, Ishiwata K, Ishii K, Inoue K
  • Journal Title: Neuroreport 19 Pages: 145-150
• [Journal Article] Lewy body pathology involves cutaneous nerves. (2008)
  • Author(s): Ikemura M, Saito Y, Sengoku R, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Murayama S
  • Journal Title: J Neuropath Exp Neurol 67 Pages: 945-953
• [Journal Article] Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis. (2008)
  • Author(s): Takahashi Y, Seki N, Ishiura H, Mitsui J, Matsukawa T, Kishino A, Onodera O, Aoki M, Shimozawa N, Murayama S, Itoyama Y, Suzuki Y, Sobue G, Nishizawa M, Goto, J, Tsuji S
  • Journal Title: Arch Neurol 65 Pages: 1326-1332
• [Journal Article] The incidence and extent of Lewy-body related alpha- synucleinopathy in human aging olfactory bulb. (2008)
  • Author(s): Sengoku R, Saito Y, Ikemura M, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Mochizuki H, Inoue K, Murayama S
  • Journal Title: J Neuropath Exp Neurol 67 Pages: 1072-1083
• [Journal Article] Presynaptic and postsynaptic nigrostriatal dopaminergic functions in multiple system atrophy (2008)
  • Author(s): Hashimoto M, Kawasaki K, Suzuki M. Mitani K, Murayama S, Mishina M, Oda K, Kimura Y, Ishiwata K, Ishii K, Inoue K
  • Journal Title: Neuroreport 19 Pages: 145-150
  • Peer Reviewed
• [Journal Article] Lewy body pathology involves cutaneous nerves (2008)
  • Author(s): Ikemura M, Saito Y, Sengoku R, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Murayama S
  • Journal Title: J Neuropath Exp Neurol 67 Pages: 945-953
  • Peer Reviewed
• [Journal Article] The incidence and extent of Lewy- body related plpha- synucleinopathy in human aging olfactory bulb (2008)
  • Author(s): Sengoku R, Saito Y, Ikemura M, Hatsuta H, Sakiyama Y. Sawabe M, Inoue K, Mochizuki H, Murayama S
  • Journal Title: J Neuropath Exp Neurol 67 Pages: 1072-7083
  • Peer Reviewed
• [Presentation] Olfactory epithelium in Lewy body disease. (2010)
  • Author(s): Funabe S, Saito Y, Hatsuta H, Sugiyama M, Murayama S
  • Organizer: 86th Annual Meeting of American Association of Neuropathologists
  • Place of Presentation: Philadelphia, PA
• [Presentation] Establishment of Japanese brain bank network for neuroloscience resrach. (2010)
  • Author(s): Murayama S, Takao M, Akatsu H, Saito Y.
  • Organizer: XVIth International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
• [Presentation] Motor dysfunction and multi-domain mild cognitive impairment in association with FUS immunopositive intra-neuronal inclusions. (2010)
  • Author(s): Takao M, Spina S, Spillantini MG, Murrell JR, Unverzagt FW, Farlow MR, Ghetti B.
  • Organizer: 7th International Conference of Frontotemporal dementia
  • Place of Presentation: Indianapolis, USA
• [Presentation] Consortium for motor neuron disease and frontotemporal dementia in Japan. (2010)
  • Author(s): Murayama S, Akiyama H, Shimizu J, Saito Y, Hasegawa M
  • Organizer: 7th International Conference of Frontotemporal dementia
  • Place of Presentation: Indianapolis, USA
• [Presentation] Laterality in argyrophilic grain disease (2009)
  • Author(s): Adachi T, Saito Y, Hatsuta H, Funabe S, Murayam S
  • Organizer: 2009 Annual Meeting of the American Association for Neuropathologists
  • Place of Presentation: San Antonio, U.S.A
  • Year and Date: 2009-07-13
• [Presentation] Development of a monoclonal antibody against the toxic conformer of the 42-mer amyloid β protein (2009)
  • Author(s): Murakami K, Horikoshi-Sakuraba Y, Murata N, Noda Y, Masuda Y, Kinoshita N, Murayama S, Shirasawa T, Shimizu T, Irie K
  • Organizer: 2009 Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Chicago, U.S.A
• [Presentation] Incidence and extent of Lewy body-related a-synucleinopathy in human aging olfactory bulb (2008)
  • Author(s): Sengoku R, Saito Y, Ikemura M, Hatsuta H, Sakiyama Y, Sawabe M, Inoue K, Mochizuki H, Murayama S.
  • Organizer: 2008 Annual Meeting of the American As sociation for Neuropathologits (The Best Clinicopathological Presentation Award)
  • Place of Presentation: San Diego
  • Year and Date: 2008-04-18
• [Book] エスクロール基本神経病理学 (2009)
  • Author(s): 村山繁雄 監訳
  • Total Pages: 375
  • Publisher: 西村書店
• [Remarks] ホームページ等
• [Remarks]
  • URL: http://www.mci.gr.jp/BrainBank
• [Remarks]
  • URL: http://www.mci.gr.jp/BrainBank
• [Remarks]
  • URL: http://www.mci.gr.jp/BrainBank/