BRAIN and NERVE－神経研究の進歩64巻2号

2012年02月発行

特集 生物学的精神医学の進歩

認知症―AD-FTDスペクトラムを中心に

著者： 武田雅俊¹

所属機関： ¹大阪大学大学院医学系研究科精神医学

ページ範囲：P.149 - P.161

文献概要

はじめに

　認知症は，記憶障害と判断力障害のために，職業上および日常生活上に著しい障害を呈する疾患と定義される。認知症の患者数は，全世界で2,430万人で，毎年460万人の新しい患者が発生している¹⁾。認知症は，その患者数の多さ，障害の大きさ，罹病期間の長さからみて，人類が取り組むべき「最大の悪性疾患」とも言える。わが国において，現時点での認知症患者数は約150万人であるが，平均余命の延長とともに増加し続けており，2050年には350万人に達すると見込まれる。

　認知症は，生物学的精神医学にとって重要な疾患の1つであることは言うまでもない。また，今後も認知症は，生物学的精神医学および精神医学全体にとって重要な疾患であり続けるであろう。その理由は，①わが国の認知症患者がこれからも増加し続けること，②認知症は，冒頭に掲げた定義（下線部）に示されるように，生物学的視点だけでは不十分であり，認知症の心理・社会的要因への理解が求められることにある。本稿では，このような認知症全体への精神医学の関与について述べた後に，代表的な認知症である，アルツハイマー病（Alzheimer disease：AD），前頭側頭型認知症（frontotemporal dementia：FTD）について概説する。

参考文献

1) Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, et al: Global prevalence of dementia: a Delphi consensus study. Lancet 366: 2112-2117, 2005

2) Breteler MM Claus JJ, van Duijn CM, Launer LJ, Hofman A: Epidemiology of Alzheimer's disease. Epidemiol Rev 14: 59-82, 1992

3) Graff-Radford NR, Woodruff BK: Frontotemporal dementia. Semin Neurol 27: 48-57, 2007

4) Nishimura T, Hariguchi S, Tada K, Takeda M. Changes in water-soluble brain protein in normal and abnormal ageing. in (Asao Hirano and Koho Miyoshi eds.) "NEUROPSYCHIATRIC DISORDERS IN THE ELDERLY", Igakushoin, Tokyo, pp.79-84, 1983

5) Nukina N, Ihara Y: One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem 99: 1541-1514, 1986

6) Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, et al: Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261: 6084-6089, 1986

7) Ihara Y, Nukina N, Miura R, Ogawara M: Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 99: 1807-1810, 1986

8) Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, et al: The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733-736, 1987

9) Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, et al: Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353: 844-846, 1991

10) Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, et al: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90: 1977-1981, 1993

11) Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, et al: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375: 754-760, 1995

12) Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, et al: Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376: 775-778, 1995

13) Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, et al: Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398: 513-517, 1999

14) Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, et al: Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17．Nature 393: 702-705, 1998

15) Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, et al: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173-177, 1999

16) Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17．Nature 442: 916-919, 2006

17) Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, et al: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349: 704-706, 1991

18) Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesgue G, et al: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375: 754-760, 1995

19) Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, et al: Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269: 973-977, 1995

20) De Strooper B: Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38: 9-12, 2003

21) Hardy J: Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci 20: 154-159, 1997

22) Bird TD: Genetic aspects of Alzheimer disease. Genet Med 10: 231-239, 2008

23) Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, et al: Apolipoprotein E: high-avidity binding to b-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90: 1977-1981, 1993

24) Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, et al: Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278: 1349-1356, 1997

25) Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921-923, 1993

26) Mahley RW, Weisgraber KH, Huang Y: Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc Natl Acad Sci U S A 103: 5644-5651, 2006

27) Drzezga A, Grimmer T, Henriksen G, Mühlan M, Pemeczky R, et al: Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72: 1487-1494, 2009

28) Reiman EM, Chen K, Liu X, Bandy D, Yu M, et al: Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 106: 6820-6825, 2009

29) Rademakers R, Hutton M: The genetics of frontotemporal lobar degeneration. Curr Neurol Neurosci Rep 7: 434-442, 2007

30) Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, et al: Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17．Nature 393: 702-705, 1998

31) Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, et al: Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36: 377-381, 2004

32) Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, et al: Mutations in the endosomal ESCRTIIIcomplex subunit CHMP2B in frontotemporal dementia. Nat Genet 37: 806-808, 2005

33) Cruts M, Gijselinck I, van der Zee J, Eugelborgts S, Wils H, et al: Null mutations in progranulin cause ubiquitinpositive frontotemporal dementia linked to chromosome 17q21．Nature 442: 920-924, 2006

34) Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17．Nature 442: 916-919, 2006

35) He Z, Bateman A: Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81: 600-612, 2003

36) He Z, Ong CH, Halper J, Bateman A: Progranulin is a mediator of the wound response. Nat Med 9: 225-229, 2003

37) Van Damme P, van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, et al: Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181: 37-41, 2008

38) Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, et al: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130-133, 2006

39) Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, et al: TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 61: 435-445, 2007

40) Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, et al: Concurrence of TDP-43, tau and a-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies. Brain Res 1184: 284-294, 2007

41) Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, et al: Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114: 221-229, 2007

42) Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, et al: TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40: 572-574, 2008

43) Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, et al: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319: 1668-1672, 2008

44) Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, et al: A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66: 839-844, 2006

45) Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, et al: Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3．Brain 129: 868-876, 2006

46) Rovelet-Lecrux A, Hanneguin D, Raux G, Le Meur N, Laguerrière A, et al: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38: 24-26, 2006

47) Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, et al: APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129: 2977-2983, 2006

48) Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM: Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology 35: 957-961, 1985

49) Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, et al: a-Synuclein locus triplication causes Parkinson's disease. Science 302: 841, 2003

50) Chartier-Harlin MC, Farrer M, Johnson J, Singleton A, Hague S, et al: a-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364: 1167-1169, 2004

51) Theuns J, Brouwers N, Engellborghs S, Sleegers K, Bogaerts V, et al: Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet 78: 936-946, 2006

52) Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, Serneels S: Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease. Brain 129: 2984-2991, 2006

53) Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, et al: A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1．Nat Med 4: 452-455, 1998

54) Rovelet-Lecrux A, Deramecourt V, Legallic S, Manrage CA, Le Ber I, et al: Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease. Neurobiol Dis 31: 41-45, 2008

55) Rovelet-Lecrux A, Lecourtois M, Thomas-Anterion C, Le Ber I, Brice A, et al: Partial deletion of the MAPT gene: a novel mechanism of FTDP-17．Hum Mutat 30: E591-E602, 2009

56) Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, et al: The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of b-site amyloid precursor protein cleaving enzyme 1．J Neurosci 28: 1213-1223, 2008

57) Lukiw WJ, Zhao Y, Cui JG: An NF-kB-sensitive micro RNA-146amediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 283: 31315-31322, 2008