Early diagnosis and treatment of Parkinson disease dementia

• Project/Area Number: 24390219
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Department of Clinical Research, National Hospital Organization Sendai Nishitaga National Hospital (2014-2015); Tohoku University (2012-2013)
• Principal Investigator: TAKEDA ATSUSHI 独立行政法人国立病院機構仙台西多賀病院(臨床研究部), その他部局等, その他 (70261534)
• Co-Investigator(Kenkyū-buntansha): HASEGAWA Takafumi 東北大学, 大学院医学系研究科, 講師 (70361079) ; KIKUCHI Akio 東北大学, 大学院医学系研究科, 助教 (80463785) ; 菅野 直人 東北大学, 大学病院, 助教 (30509550)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2015: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: シヌクレイノパチー / 分子イメージング / レビー小体 / グリア細胞質封入体 / シヌクレイン

Outline of Final Research Achievements

Dementia is now known to be the greatest risk factor for poor prognosis of Parkinson disease (PD). Thus an early diagnosis and therapeutic intervention for cognitive impairments may enable to improve the long-term prognosis of PD. In this project, we investigated the distribution and propagation process of synuclein aggregation in PD brain by using the [11C]BF-227 PET. Nine of 19 PD cases showed high uptake in limbic system such as orbitofrontal area, amygdale, and cingulate cortex. The areas of high uptake were increasing by time-dependent manner. Other cases showed little of BF-227 signals. From these results, we speculate that there may be two patterns of synuclein deposition in PD, that is, limbic type with high BF-227 signals and brainstem type without apparent BF-227 uptake, although further study by using new probes more specific for synuclein aggregation are needed to confirm the present results.

Research Products

• [Journal Article] Loss of awareness of hyposmia is associated with mild cognitive impairment in Parkinson's disease. (2016)
  • Author(s): Kawasaki I., Baba T., Takeda A., Mori E.
  • Journal Title: Parkinsonism & related dis. Volume: 22 Pages: 74-79
  • DOI: 10.1016/j.parkreldis.2015.11.015
  • Peer Reviewed
• [Journal Article] On the utility of MIBG SPECT/CT in evaluating cardiac sympathetic dysfunction in Lewy body diseases (2016)
  • Author(s): Odagiri H, Baba T, Nishio Y, Iizuka O, Matsuda M, Inoue K, Kikuchi A, Hasegawa T, Aoki M, Takeda A, Taki Y, Mori E
  • Journal Title: PLoS One Volume: 11(4) Issue: 4 Pages: 0152746-0152746
  • DOI: 10.1371/journal.pone.0152746
  • Peer Reviewed / Open Access
• [Journal Article] ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways (2016)
  • Author(s): Oshima R, Hasegawa T, Tamai K, Sugeno N, Yoshida S, Kobayashi J, Kikuchi A, Baba T, Futatsugi A, Sato I, Satoh K, Takeda A, Aoki M and Tanaka N
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 24997-24997
  • DOI: 10.1038/srep24997
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Subgroup differences in “brain-type” transferrin and alpha-synuclein in Parkinson's disease and multiple system atrophy (2016)
  • Author(s): A Yoshihara, M Fukatsu, K Hoshi, Y Hashimoto, et. al
  • Journal Title: The Journal of Biochemistry Volume: 159 Issue: 2 Pages: 87-91
  • DOI: 10.1093/jb/mvw015
  • Description: 未定
  • Peer Reviewed
• [Journal Article] Pareidolia in Parkinson's disease without dementia: A positron emission tomography study. (2015)
  • Author(s): Uchiyama M., Nishio Y., Yokoi K., Hosokai Y., Takeda A., Mori E.
  • Journal Title: Parkinsonism & relat. disord Volume: 21 Issue: 6 Pages: 603-609
  • DOI: 10.1016/j.parkreldis.2015.03.020
  • Peer Reviewed
• [Journal Article] K63-linked ubiquitination by E3 Ubiquitin Ligase Nedd4-1 facilitates endosomal sequestration of internalized alpha-synuclein. (2014)
  • Author(s): Sugeno N, Hasegawa T, Tanaka N, Fukuda M, Wakabayashi K, Oshima R, Konno M, Miura E, Kikuchi A, Baba T, Anan T, Nakao M, Geisler S, Aoki M, Takeda A.
  • Journal Title: J Biol Chem Volume: 289 Issue: 26 Pages: 18137-18151
  • DOI: 10.1074/jbc.m113.529461
  • Peer Reviewed / Open Access
• [Journal Article] VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease. (2014)
  • Author(s): Miura E, Hasegawa T, Konno M, Suzuki M, Sugeno N, Fujikake N, Geisler S, Tabuchi M, Oshima R, Kikuchi A, Baba T, Wada K, Nagai Y, Takeda A, Aoki M.
  • Journal Title: Neurobio Dis Volume: 71 Pages: 1-13
  • DOI: 10.1016/j.nbd.2014.07.014
  • Peer Reviewed
• [Journal Article] 1.Neural Substrates of Cognitive Subtypes in Parkinson's Disease: A 3-Year Longitudinal Study (2014)
  • Author(s): Shoji Y¸ Nishio Y, Baba T, Uchiyama M, Yokoi K, Ishioka T, Hosokai Y, Hirayama K, Fukuda H, Aoki M, Hasegawa T, Takeda A, Mori E.
  • Journal Title: PLoS ONE Volume: 9(10) Issue: 10 Pages: e110547-e110547
  • DOI: 10.1371/journal.pone.0110547
  • Peer Reviewed / Open Access
• [Journal Article] Olfactory dysfunction and dementia in Parkinson's disease. (2014)
  • Author(s): Takeda A, Baba T, Kikuchi A, Hasegawa T, Sugeno N, Konno M, Miura E, Mori E.
  • Journal Title: J Parkinsons Dis Volume: 4 Issue: 2 Pages: 181-187
  • DOI: 10.3233/jpd-130277
  • Peer Reviewed
• [Journal Article] Cognitive impairment in multiple system atrophy: A position statement by the Neuropsychology Task Force of the MDS multiple system atrophy (MODIMSA) Study Group. (2014)
  • Author(s): Stankovic I., Krismer F., Jesic A., Antonini A., Benke T., Brown RG., Burn DJ., Holton JL., Kaufmann H., Kostic VS., Ling H., Meissner WG., Poewe W., Semnic M., Seppi K., Takeda A., Weintraub D., Wenning GK.
  • Journal Title: Movement Disorders Volume: 29 Issue: 7 Pages: 857-867
  • DOI: 10.1002/mds.25880
  • Peer Reviewed
• [Journal Article] Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in Parkinson's disease: a cross-sectional and 3-year longitudinal cohort study (2013)
  • Author(s): Akio Kikuchi, Toru Baba, Takafumi Hasegawa, Michiko Kobayashi, Naoto Sugeno, Masatoshi Konno, Emiko Miura, Yoshiyuki Hosokai, Toshiyuki Ishioka, Yoshiyuki Nishio, Kazumi Hirayama, Kyoko Suzuki, Masashi Aoki, ShokiTakahashi, Hiroshi Fukuda, Yasuto Itoyama, Etsuro Mori, Atsushi Takeda
  • Journal Title: BMJ Open Volume: 3 Issue: 3 Pages: e002249-e002249
  • DOI: 10.1136/bmjopen-2012-002249
  • Peer Reviewed
• [Journal Article] Pathogenesis of Multiple system atrophy. (2013)
  • Author(s): Hasegawa T, Kikuchi A, Takeda A.
  • Journal Title: Neurol Clin Neurosci Volume: 1 (6) Issue: 6 Pages: 189-194
  • DOI: 10.1111/ncn3.57
  • Peer Reviewed
• [Journal Article] Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease : a 3-year longitudinal study (2012)
  • Author(s): BabaT, Kikuchi A, Hirayama K, Nishio Y, Hosokai Y, Kanno S, Hasegawa T, Sugeno N, Konno M, Suzuki K, et al
  • Journal Title: Brain Volume: 135 Issue: 1 Pages: 162-169
  • DOI: 10.1093/brain/awr321
  • Peer Reviewed
• [Journal Article] Attentional Set-Shifting Deficit in Parkinson's Disease Is Associated with Prefrontal Dysfunction: An FDG-PET Study (2012)
  • Author(s): Yoichi Sawada, Yoshiyuki Nishio, Kyoko Suzuki, Kazumi Hirayama, Atsushi Takeda, Yoshiyuki Hosokai, Toshiyuki Ishioka, Yasuto Itoyama, Shoki Takahashi, Hiroshi Fukuda, Etsuro Mori
  • Journal Title: PLoS ONE Volume: 7(6) Issue: 6 Pages: e38498-e38498
  • DOI: 10.1371/journal.pone.0038498
  • Peer Reviewed
• [Journal Article] Cholinergic deficit and response to donepezil therapy in Parkinson's disease with dementia (2012)
  • Author(s): Hiraoka K, Okamura N, Funaki Y, Hayashi A, Tashiro M, Hisanaga K, Fujii T, Takeda A, Y anai K, Iwata R, Mori E
  • Journal Title: Eur Neurol Volume: 68 Issue: 3 Pages: 137-143
  • DOI: 10.1159/000338774
  • Peer Reviewed
• [Journal Article] Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. (2012)
  • Author(s): Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A, Fiesel FC, Sasaki T, Aoki M, Itoyama Y, Takeda A.
  • Journal Title: Mol Neurodegener Volume: 7 Issue: 1 Pages: 38-38
  • DOI: 10.1186/1750-1326-7-38
  • Peer Reviewed
• [Presentation] 難治性の運動症状や非運動症状にどう対応するか? (2015)
  • Author(s): 武田篤
  • Organizer: 第33回日本神経治療学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-26
  • Invited
• [Presentation] パーキンソン病に於けるコリン系と認知機能、そしてレビー小体型認知症との関連 (2015)
  • Author(s): 武田篤
  • Organizer: 第69回国立病院総合医学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] パーキンソン病における脳内α-シヌクレイン蛋白凝集体のPETによる画像化 (2015)
  • Author(s): 198)菊池 昭夫、馬場 徹、長谷川 隆文、菅野 直人、今野 昌俊、三浦 永美子、大嶋 龍司、岡村 信行、古本 祥三、谷内 一彦、田代 学、工藤 幸司、糸山 泰人、武田 篤、青木 正志
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20
• [Presentation] Hot Topics in Parkinson Disease (2015)
  • Author(s): Takeda A.
  • Organizer: The14th International Parkinson Disease Symposium in Takamatsu
  • Place of Presentation: Takamatsu, Japan
  • Year and Date: 2015-02-27 – 2015-03-01
  • Invited
• [Presentation] In vivo visualization of α-synuclein deposition by carbon-11-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)−6-(2-[fluoro]ethoxy)benzoxazole positron emission tomography in Parkinson's disease (2014)
  • Author(s): Kikuchi A. Okamura N. Tashiro M. Hasegawa T. Sugeno N. Baba T. Konno M. Miura E. Oshima R. Furumoto S. Funaki Y. Iwata R. Takahashi S. Fukuda H. Arai H. Kudo Y. Yanai K. Itoyama Y. Aoki M. Takeda A.
  • Organizer: 18th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-07 – 2014-06-12
• [Presentation] Cognitive impairment in multiple system atrophy: A position statement by the neuropsychology task force of the MDS multiple system atrophy (MODIMSA) study group (2014)
  • Author(s): Stankovic I. Krismer F. Jesic A. Antonini A. Benke T. Brown R.G. Burn D.J. Holton J.L. Kaufmann H. Kostic V.S. Ling H. Meissner W.G. Poewe W. Semnic M. Seppi K. Takeda A. Weintraub D. Wenning G.K.
  • Organizer: 18th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-07 – 2014-06-12
• [Presentation] Exome sequencing of Parkinson's disease in order to identify genetic variants with high disease-risk (2014)
  • Author(s): Satake W. Ando Y. Tomiyama H. Kashihara K. Mochizuki H. Murayama S. Takeda A. Hasegawa K. Tsuji S. Yamamoto M. Murata M. Hattori N. Toda T.
  • Organizer: 18th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-07 – 2014-06-12
• [Presentation] Functional ESCRT machinery is required for the clearance of aggregate-prone proteins associated with neurodegenerative diseases (2014)
  • Author(s): Oshima R. Hasegawa T. Sugeno N. Konno M. Miura E. Kikuchi A. Tamai K. Takeda A. Tanaka N. Aoki M.
  • Organizer: 18th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-07 – 2014-06-12
• [Presentation] K63-linked ubiquitination by Nedd4 facilitates endosomal sequestration of internalized alpha-synuclein, 18th International Congress of Parkinson’s Disease and Movement Disorders (2014)
  • Author(s): Sugeno N. Hasegawa T. Tanaka N. Oshima R. Konno M. Miura E. Kikuchi A. Baba T. Fukuda M. Geisler S. Aoki M. Takeda A.,
  • Organizer: 18th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-07 – 2014-06-12
• [Presentation] Severe hyposmia is a prodromal symptom of dementia in Parkinson disease (2013)
  • Author(s): Takeda A.
  • Organizer: 9th International congress on mental dysfunction & other non-motor features in Parkinson’s disease and related disorders
  • Place of Presentation: Seoul, South Korea
  • Invited
• [Presentation] Differentiating Parkinson's disease from multiple system atrophy by [123I] meta-iodobenzylguanidine myocardial scintigraphy and olfactory test (2013)
  • Author(s): Kikuchi A. Baba T. Hasegawa T. Sugeno N. Konno M. Aoki M. Takeda A.
  • Organizer: 17th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Sydney, Australia
• [Presentation] Nedd4 E3 ubiquitin ligase facilitates the endosomal targeting of alpha-synuclein (2013)
  • Author(s): Sugeno N. Hasegawa T. Konno M. Miura E. Kikuchi A. Aoki M. Takeda A.
  • Organizer: 17th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Sydney, Australia
• [Presentation] RNAi-mediated knockdown of VPS35 impairs α-synuclein degradation by inhibiting the maturation of cathepsin D (2013)
  • Author(s): Miura E. Hasegawa T. Konno M. Sugeno N. Kikuchi A. Baba T. Aoki M. Takeda A.
  • Organizer: 17th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Sydney, Australia
• [Presentation] RNAi-mediated silencing of VPS35 exacerbates phenotypic and locomotor abnormalities in α-synuclein transgenic drosophila (2013)
  • Author(s): Hasegawa T. Konno M. Miura E. Sugeno N. Nagai Y. Fujikake N. Suzuki M. Kikuchi A. Aoki M. Takeda A.
  • Organizer: 17th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Sydney, Australia
• [Presentation] Search for rare-variant risks of Parkinson's disease by sequencing of candidate genes and exome sequencing (2013)
  • Author(s): Satake W. Ando Y. Tomiyama H. Takeda A. Hasegawa K. Yamamoto M. Murata M. Hattori N. Toda T.
  • Organizer: 17th International Congress of Parkinson’s Disease and Movement Disorders
  • Place of Presentation: Sydney, Australia
• [Presentation] The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein (2012)
  • Author(s): Hasegawa T., Konno M., Baba T., Sugeno N., Kikuchi A., Miura E., Takeda A.
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Dublin, Ireland
• [Presentation] Severe olfactory dysfunction is predictive of dementia associated with Parkinson's disease : A 3-year longitudinal study (2012)
  • Author(s): Baba T., Kikuchi A., Hirayama K., Nishio Y., Hosokai Y., Kanno S., Hasegawa T., Sugeno N., Konno M., Miura E., Mori E., Takeda A.
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Dublin, Ireland
• [Presentation] Dynamin GTPase activity decreases alpha-synuclein uptake in neuronal and oligodendroglial cells (2012)
  • Author(s): Konno M., Hasegawa T., Baba T., Miura E., Sugeno N., Kikuchi A., Aoki M., Takeda A.
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Dublin, Ireland
• [Presentation] Nedd4 participates in the internalization process of alpha-synuclein (2012)
  • Author(s): Sugeno N., Hasegawa T., Konno M., Miura E., Baba T., Kikuchi A., Aoki M., Takeda A.
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Dublin, Ireland
• [Presentation] Neural basis of memory impairment in Parkinson's disease: A longitudinal PET study (2012)
  • Author(s): Shoji Y., Nishio Y, Takeda A., Uchiyama M., Kashinoura T., Hosokai Y., Fukuda H., Mori E.
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Dublin, Ireland
• [Presentation] Japanese 2nd GWAS identifies strong association at a novel risk locus and MCCC1 for Parkinson's disease (2012)
  • Author(s): Satake W., Yamamoto K, Ando Y., Takeda A., Tomiyama H., Kawakami H., Hasegawa K., Obata F., Watanabe M., Tamaoka A., Nakashima K., Sakoda S., Yamamoto M., Hattori N., Murata M., Nakamura Y., Toda T.
  • Organizer: 16th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Dublin, Ireland
• [Book] パーキンソン病実践診療マニュアル (2016)
  • Author(s): 武田篤（編著）
  • Total Pages: 280
  • Publisher: 中外医学社
• [Book] Visual function in Parkinson’s disease. in Chaudhuri KR., Tolosa E, Schapira AHV., & Poewe W. (ed.); Non-motor symptoms of Parkinson’s disease 2nded. (2014)
  • Author(s): Baba T., Estrada-Bellmann I., Mori E., Takeda A.
  • Total Pages: 11
  • Publisher: Oxford University Press