Neurological Surgery 脳神経外科42巻4号

2014年04月発行

総説

脳アミロイド血管症の病理

著者： 中里洋一¹

所属機関： ¹日高病院病理部病理診断科

ページ範囲：P.299 - P.310

Ⅰ．はじめに

　脳アミロイド血管症（cerebral amyloid angiopathy：CAA）は頭蓋内の血管にアミロイドが沈着するために発生するさまざまな脳循環障害性疾患の総称である．人口の高齢化に伴い本症の罹患率は増えており，特に非高血圧性脳出血の主な原因として本症は重要度を増している．沈着するアミロイドは数種類に及び，遺伝性のものと孤発性のものがある．アミロイドの沈着に伴い，脳血管は脆弱性と透過性を増し，あるいは内腔が狭窄してさまざまな循環障害性病態を引き起こす．主なものは脳葉型の大出血であるが，ほかにも皮質下出血，皮質微小梗塞，大脳白質病変，肉芽腫性血管炎などがある．本稿では，CAAの概要について述べ，次いでCAAの病理について解説を行う．

参考文献

1) Attems J, Jellinger KA, Lintner F：Alzheimer's disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol 110：222-231, 2005

2) Attems J, Jellinger K, Thal DR, Van Nostrand W：Review：sporadic cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 37：75-93, 2011

3) Cadavid D, Mena H, Koeller K, Frommelt RA：Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 59：768-773, 2000

4) CFAS（Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study）：Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 357：169-175, 2001

5) Charidimou A, Jäger HR, Werring DJ：Cerebral microbleed detection and mapping：principles, methodological aspects and rationale in vascular dementia. Exp Gerontol 47：843-852, 2012

6) Feldman HH, Maia LF, Mackenzie IR, Forster BB, Martzke J, Woolfenden A：Superficial siderosis：a potential diagnostic marker of cerebral amyloid angiopathy in Alzheimer disease. Stroke 39：2894-2897, 2008

7) Frackowiak J, Zoltowska A, Wisniewski HM：Non-fibrillar beta-amyloid protein is associated with smooth muscle cells of vessel walls in Alzheimer disease. J Neuropathol Exp Neurol 53：637-645, 1994

8) Fukumoto H, Rosene DL, Moss MB, Raju S, Hyman BT, Irizarry MC：Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am J Pathol 164：719-725, 2004

9) Gilbert JJ, Vinters HV：Cerebral amyloid angiopathy：incidence and complications in the aging brain. I. Cerebral hemorrhage. Stroke 14：915-923, 1983

10) Glenner GG, Henry JH, Fujihara S：Congophilic angiopathy in the pathogenesis of Alzheimer's degeneration. Ann Pathol 1：120-129, 1981

11) Hersh LB, Rodgers DW：Neprilysin and amyloid beta peptide degradation. Curr Alzheimer Res 5：225-231, 2008

12) 廣畑美枝，山田正仁：脳アミロイドアンギオパチーの疫学と病態．医学のあゆみ229：409-414, 2009

13) Holland CM, Smith EE, Csapo I, Gurol ME, Brylka DA, Killiany RJ, Blacker D, Albert MS, Guttmann CR, Greenberg SM：Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke 39：1127-1133, 2008

14) Ikeda M, Hirayanagi K, Arai M, Kakuda S, Makioka K, Furuta N, Takai E, Kasahara H, Tsukagoshi S, Fujita Y, Amari M, Takatama M, Nakazato Y, Okamoto K：Encephalopathy with amyloid angiopathy and numerous amyloid plaques with low levels of CSF Abeta1-40/Abeta1-42. Amyloid 19：186-190, 2012

15) Inagawa T, Ohbayashi N, Takechi A, Shibukawa M, Yahara K：Primary intracerebral hemorrhage in Izumo City, Japan：incidence rates and outcome in relation to the site of hemorrhage. Neurosurgery 53：1283-1297；discussion 1297-1298, 2003

16) Kimberly WT, Gilson A, Rost NS, Rosand J, Viswanathan A, Smith EE, Greenberg SM：Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy. Neurology 72：1230-1235, 2009

17) Kinnecom C, Lev MH, Wendell L, Smith EE, Rosand J, Frosch MP, Greenberg SM：Course of cerebral amyloid angiopathy-related inflammation. Neurology 68：1411-1416, 2007

18) Knudsen KA, Rosand J, Karluk D, Greenberg SM：Clinical diagnosis of cerebral amyloid angiopathy：validation of the Boston criteria. Neurology 56：537-539, 2001

19) Kumar S, Goddeau RP Jr, Selim MH, Thomas A, Schlaug G, Alhazzani A, Searls DE, Caplan LR：Atraumatic convexal subarachnoid hemorrhage：clinical presentation, imaging patterns, and etiologies. Neurology 74：893-899, 2010

20) Levy M, Turtzo C, Llinas RH：Superficial siderosis：a case report and review of the literature. Nat Clin Pract Neurol 3：54-58；quiz 59, 2007

21) Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, van Buchem MA, Bruckmann H, Greenberg SM：Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 74：1346-1350, 2010

22) Linn J, Wollenweber FA, Lummel N, Bochmann K, Pfefferkorn T, Gschwendtner A, Bruckmann H, Dichgans M, Opherk C：Superficial siderosis is a warning sign for future intracranial hemorrhage. J Neurol 260：176-181, 2013

23) Maeda A, Yamada M, Itoh Y, Otomo E, Hayakawa M, Miyatake T：Computer-assisted three-dimensional image analysis of cerebral amyloid angiopathy. Stroke 24：1857-1864, 1993

24) Masuda J, Tanaka K, Ueda K, Omae T：Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan. Stroke 19：205-210, 1988

25) Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S：Abeta-degrading enzymes in Alzheimer's disease. Brain Pathol 18：240-252, 2008

26) Neumann MA：Combined amyloid vascular changes and argyrophilic plaques in the central nervous system. J Neuropathol Exp Neurol 19：370-382, 1960

27) Oh U, Gupta R, Krakauer JW, Khandji AG, Chin SS, Elkind MS：Reversible leukoencephalopathy associated with cerebral amyloid angiopathy. Neurology 62：494-497, 2004

28) Oide T, Tokuda T, Takei Y, Takahashi H, Ito K, Ikeda S：Serial CT and MRI findings in a patient with isolated angiitis of the central nervous system associated with cerebral amyloid angiopathy. Amyloid 9：256-262, 2002

29) Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R, Thal LJ：Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol 52：702-708, 1995

30) Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, Rogaeva E, Black SE：Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 65：790-795, 2008

31) Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ：Cerebral amyloid angiopathy and cognitive function：the HAAS autopsy study. Neurology 58：1629-1634, 2002

32) Pluta R, Furmaga-Jabłońska W, Maciejewski R, Ułamek-Kozioł M, Jabłoński M：Brain ischemia activates beta- and gamma-secretase cleavage of amyloid precursor protein：significance in sporadic Alzheimer's disease. Mol Neurobiol 47：425-434, 2013

33) Revesz T, Holton JL, Lashley T, Plant G, Rostagno A, Ghiso J, Frangione B：Sporadic and familial cerebral amyloid angiopathies. Brain Pathol 12：343-357, 2002

34) Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL：Cerebral amyloid angiopathies：a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol 62：885-898, 2003

35) Revesz T, Holton JL, Lashley T, Plant G, Frangione B, Rostagno A, Ghiso J：Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol 118：115-130, 2009

36) Richard E, Carrano A, Hoozemans JJ, van Horssen J, van Haastert ES, Eurelings LS, de Vries HE, Thal DR, Eikelenboom P, van Gool WA, Rozemuller AJ：Characteristics of dyshoric capillary cerebral amyloid angiopathy. J Neuropathol Exp Neurol 69：1158-1167, 2010

37) Scholz W：Studien zur Pathologie der Hirngefässe. II. Die drusige Entartung der Hirnarterien und -capillaren. Z gesamte Neurol Psychiatr 162：694-715, 1938

38) Scolding NJ, Joseph F, Kirby PA, Mazanti I, Gray F, Mikol J, Ellison D, Hilton DA, Williams TL, MacKenzie JM, Xuereb JH, Love S：Abeta-related angiitis：primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128：500-515, 2005

39) Soontornniyomkij V, Lynch MD, Mermash S, Pomakian J, Badkoobehi H, Clare R, Vinters HV：Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Pathol 20：459-467, 2010

40) Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W：Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A 103：18727-18732, 2006

41) Takeda S, Yamazaki K, Miyakawa T, Onda K, Hinokuma K, Ikuta F, Arai H：Subcortical hematoma caused by cerebral amyloid angiopathy：does the first evidence of hemorrhage occur in the subarachnoid space? Neuropathology 23：254-261, 2003

42) Takeda S, Hinokuma K, Yamazaki K, Onda K, Miyakawa T, Ikuta F, Arai H：The hemorrhage caused by sporadic-type cerebral amyloid angiopathy occurs primarily in the cerebral sulci. Neuropathology 32：38-43, 2012

43) Tanskanen M, Kiuru-Enari S, Tienari P, Polvikoski T, Verkkoniemi A, Rastas S, Sulkava R, Paetau A：Senile systemic amyloidosis, cerebral amyloid angiopathy, and dementia in a very old Finnish population. Amyloid 13：164-169, 2006

44) Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H：Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61：282-293, 2002

45) Thal DR, Ghebremedhin E, Orantes M, Wiestler OD：Vascular pathology in Alzheimer disease：correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62：1287-1301, 2003

46) Thal DR, Griffin WS, Braak H：Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease. J Cell Mol Med 12：1848-1862, 2008

47) Tian J, Shi J, Smallman R, Iwatsubo T, Mann DM：Relationships in Alzheimer's disease between the extent of Abeta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen. Neuropathol Appl Neurobiol 32：332-340, 2006

48) Ueda K, Hasuo Y, Kiyohara Y, Wada J, Kawano H, Kato I, Fujii I, Yanai T, Omae T, Fujishima M：Intracerebral hemorrhage in a Japanese community, Hisayama：incidence, changing pattern during long-term follow-up, and related factors. Stroke 19：48-52, 1988

49) Velliquette RA, O'Connor T, Vassar R：Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice：possible early events in Alzheimer's disease pathogenesis. J Neurosci 25：10874-10883, 2005

50) Vinters HV, Gilbert JJ：Cerebral amyloid angiopathy：incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14：924-928, 1983

51) Vinters HV：Cerebral amyloid angiopathy. A critical review. Stroke 18：311-324, 1987

52) Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr：Cerebral amyloid angiopathy without and with cerebral hemorrhages：a comparative histological study. Ann Neurol 30：637-649, 1991

53) Wakai S, Kumakura N, Nagai M：Lobar intracerebral hemorrhage. A clinical, radiographic, and pathological study of 29 consecutive operated cases with negative angiography. J Neurosurg 76：231-238, 1992

54) Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE：Cerebral amyloid angiopathy：amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol 153：725-733, 1998

55) Weller RO, Preston SD, Subash M, Carare RO：Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease. Alzheimers Res Ther 1：6, 2009

56) Yamada M, Tsukagoshi H, Otomo E, Hayakawa M：Cerebral amyloid angiopathy in the aged. J Neurol 234：371-376, 1987

57) Yamada M, Itoh Y, Otomo E, Hayakawa M, Miyatake T：Subarachnoid haemorrhage in the elderly：a necropsy study of the association with cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry 56：543-547, 1993

58) Yamada M：Cerebral amyloid angiopathy：an overview. Neuropathology 20：8-22, 2000

59) Yamada M：Risk factors for cerebral amyloid angiopathy in the elderly. Ann N Y Acad Sci 977：37-44, 2002

60) Yamaguchi H, Yamazaki T, Lemere CA, Frosch MP, Selkoe DJ：Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease. An immunoelectron microscopic study. Am J Pathol 141：249-259, 1992

61) Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ：Cerebral amyloid angiopathy in the elderly：vessel walls changes and relationship with dementia. Acta Neuropathol 106：367-373, 2003

62) Zhu YC, Chabriat H, Godin O, Dufouil C, Rosand J, Greenberg SM, Smith EE, Tzourio C, Viswanathan A：Distribution of white matter hyperintensity in cerebral hemorrhage and healthy aging. J Neurol 259：530-536, 2012

63) Zlokovic BV：Vascular disorder in Alzheimer's disease：role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev 54：1553-1559, 2002