Neurological Surgery 脳神経外科47巻4号

2019年04月発行

総説

脳神経外科手術におけるフレイルの問題

著者： 森健太郎¹

所属機関： ¹防衛医科大学校脳神経外科学講座

ページ範囲：P.389 - P.403

Ⅰ．はじめに
　近年，日本は世界に例のない速さで高齢化が進み，どの国もこれまで経験したことがない超高齢社会を迎えた．さらに，「団塊の世代」が75歳以上の後期高齢者となる2025年には，全人口に占める後期高齢者の割合が約18%に達し，65歳以上の高齢者の割合は30%を超えると予想されている．高齢者人口の増加に伴い，高齢者に特有な疾患の診療機会の増加が予想される．例えば，高齢者の原発性脳腫瘍の代表格である悪性神経膠腫については，患者の平均年齢は65歳であり，75歳以降の後期高齢者層で最大の発生率を示すと言われている²⁵⁾．
　一方，高齢者層は，健康な人から要介護状態の人まで，さまざまな健康状態の人々で構成されているという特徴もある．健康と要介護状態の間には種々の段階の虚弱（フレイル）状態の人が存在する．すなわち，寿命の延伸とともに，高齢者層は身体的・精神的・社会的に非常に多様化しているのである．高齢者層の多様化に伴い，これまでのように疾患と年齢だけで治療適応や予後予測をすることは困難となりつつあり，高齢患者に関しては，今までの治療ガイドラインでは対応が不十分となる可能性がある．本稿では，フレイルについて概説するとともに，脳神経外科領域の各疾患とフレイルとの関係について，特に高齢者に好発する疾患を中心に解説し，その問題点についても提起する．

参考文献

1) Abbott AL：Medical（nonsurgical）intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis：results of a systematic review and analysis. Stroke 40：e573-e583, 2009

2) Abe Y, Maruyama K, Yokoya S, Noguchi A, Sato E, Nagane M, Shiokawa Y：Outcomes of chronic subdural hematoma with preexisting comorbidities causing disturbed consciousness. J Neurosurg 126：1042-1046, 2017

3) Afilalo J, Eisenberg MJ, Morin JF, Bergman H, Monette J, Noiseux N, Perrault LP, Alexander KP, Langlois Y, Dendukuri N, Chamoun P, Kasparian G, Robichaud S, Gharacholou SM, Boivin JF：Gait speed as an incremental predictor of mortality and major morbidity in elderly patients undergoing cardiac surgery. J Am Coll Cardiol 56：1668-1676, 2010

4) Ali R, Schwalb JM, Nerenz DR, Antoine HJ, Rubinfeld I：Use of the modified frailty index to predict 30-day morbidity and mortality from spine surgery. J Neurosurg Spine 25：537-541, 2016

5) Amrock LG, Deiner S：The implication of frailty on preoperative risk assessment. Curr Opin Anaesthesiol 27：330-335, 2014

6) Arca R, Ricchi V, Murgia D, Melis M, Floris F, Mereu A, Contu P, Marrosu F, Melis M, Cossu G：Parkinsonism and dementia are negative prognostic factors for the outcome of subdural hematoma. Neurol Sci 37：1299-1303, 2016

7) Asghar M, Adhiyaman V, Greenway MW, Bhowmick BK, Bates A：Chronic subdural haematoma in the elderly--a North Wales experience. J R Soc Med 95：290-292, 2002

8) Attenello FJ, Wang K, Wen T, Cen SY, Kim-Tenser M, Amar AP, Sanossian N, Giannotta SL, Mack WJ：Health disparities in time to aneurysm clipping/coiling among aneurysmal subarachnoid hemorrhage patients：a national study. World Neurosurg 82：1071-1076, 2014

9) Barker FG 2nd, Chang SM, Gutin PH, Malec MK, McDermott MW, Prados MD, Wilson CB：Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 42：709-723, 1998

10) Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE, Spence JD：Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 339：1415-1425, 1998

11) Bekelis K, Missios S, Mackenzie TA, Desai A, Fisher A, Labropoulos N, Roberts DW：Predicting inpatient complications from cerebral aneurysms clipping：the Nationwide Inpatient Sample 2005-2009. J Neurosurg 120：591-598, 2014

12) Boogaarts HD, Duarte Conde MP, Janssen E, van Nuenen WFM, de Vries J, Donders R, Westert GP, Grotenhuis JA, Bartels RH：The value of the Charlson Co-morbidity Index in aneurysmal subarachnoid haemorrhage. Acta Neurochir（Wien）156：1663-1667, 2014

13) Brinjikji W, Rabinstein AA, Lanzino G, Kallmes DF, Cloft HJ：Effect of age on outcomes of treatment of unruptured cerebral aneurysms：a study of the National Inpatient Sample 2001-2008. Stroke 42：1320-1324, 2011

14) Chambers BR, Donnan GA：Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 19：CD001923, 2005

15) Charest-Morin R, Street J, Zhang H, Roughead T, Ailon T, Boyd M, Dvorak M, Kwon B, Paquette S, Dea N, Fisher CG, Fexman AM：Frailty and sarcopenia do not predict adverse events in an elderly population undergoing non-complex primary elective surgery for degenerative conditions of the lumbar spine. Spine J 18：245-254, 2018

16) Charlson ME, Pompei P, Ales KL, MacKenzie CR：A new method of classifying prognostic comorbidity in longitudinal studies：development and validation. J Chronic Dis 40：373-383, 1987

17) Chung CP, Chou KH, Chen WT, Liu LK, Lee WJ, Chen LK, Lin CP, Wang PN：Cerebral microbleeds are associated with physical frailty：a community-based study. Neurobiol Aging 44：143-150, 2016

18) Cloney M, D'Amico R, Lebovic J, Nazarian M, Zacharia BE, Sisti MB, Bruce JN, McKhann GM, Iwamoto FM, Sonabend AM：Frailty in geriatric glioblastoma patients：a predictor of operative morbidity and outcome. World Neurosurg 89：362-367, 2016

19) Collard RM, Boter H, Schoevers RA, Oude Voshaar RC：Prevalence of frailty in community-dwelling older persons：a systematic review. J Am Geriatr Soc 60：1487-1492, 2012

20) Comerota AJ, Salles-Cunha SX, Daoud Y, Jones L, Beebe HG：Gender differences in blood velocities across carotid stenoses. J Vasc Surg 40：939-944, 2004

21) Committee for the Asymptomatic Carotid Atherosclerosis Study：Endarterectomy for asymptomatic carotid artery stenosis. JAMA 273：1421-1428, 1995

22) Dasenbrock HH, Angriman F, Smith TR, Gormley WB, Frerichs KU, Aziz-Sultan MA, Du R：Readmission after aneurysmal subarachnoid hemorrhage：a nationwide readmission database analysis. Stroke 48：2383-2390, 2017

23) Debette S, Markus HS：The clinical importance of white matter hyperintensities on brain magnetic resonance imaging：systematic review and meta-analysis. BMJ 341：c3666, 2010

24) Doehner W, Schenkel J, Anker SD, Springer J, Audebert HJ：Overweight and obesity are associated with improved survival, functional outcome, and stroke recurrence after acute stroke or transient ischaemic attack：observations from the TEMPiS trial. Eur Heart J 34：268-277, 2013

25) Dolecek TA, Propp JM, Stroup NE, Kruchko C：CBTRUS statistical report：primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 14（suppl 5）：v1-v49, 2012

26) Dorhout Mees SM, van Dijk GW, Algra A, Kempink DRJ, Rinkel GJE：Glucose levels and outcome after subarachnoid hemorrhage. Neurology 61：1132-1133, 2003

27) Elixhauser A, Steiner C, Harris DR, Coffey RM：Comorbidity measures for use with administrative data. Med Care 36：8-27, 1998

28) Flexman AM, Charest-Morin R, Stobart L, Street J, Ryerson CJ：Frailty and postoperative outcomes in patients undergoing surgery for degenerative spine disease. Spine J 16：1315-1323, 2016

29) Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA；Cardiovascular Health Study Collaborative Research Group：Frailty in older adults：evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56：M146-156, 2001

30) 藤岡正導，松角康彦，賀来素之，桜間信義，野中信仁，三浦義一：慢性硬膜下血腫100例の臨床とCT—症状発現とCT所見における血腫発育過程—．Neurol Med Chir（Tokyo）21：1153-1160, 1981

31) フレイルに関する日本老年医学会からのステートメント（平成26年5月）　https://www.jpn-geriat-soc.or.jp/info/topics/pdf/20140513_01_01.pdf

32) Galea JP, Dulhanty L, Patel HC；UK and Ireland Subarachnoid Hemorrhage Database Collaborators：Predictors of outcome in aneurysmal subarachnoid hemorrhage patients：observations from a multicenter data set. Stroke 48：2958-2963, 2017

33) García-González JJ, García-Peña C, Franco-Marina F, Gutiérrez-Robledo LM：A frailty index to the predict mortality risk in a population of senior Mexican adults. BMC Geriatr 9：47, 2009

34) Gordon EH, Peel NM, Samanta M, Theou O, Howlett SE, Hubbard RE：Sex differences in frailty：a systematic review and meta-analysis. Exp Gerontol 89：30-40, 2017

35) Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, Thomas D；MRC Asymptomatic Carotid Surgery Trial（ACST）Collaborative Group：Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms：randomised controlled trial. Lancet 363：1491-1502, 2004

36) Herrmann LL, Le Masurier M, Ebmeier KP：White matter hyperintensities in late life depression：a systematic review. J Neurol Neurosurg Psychiatry 79：619-624, 2008

37) Hotta K, Sorimachi T, Honda Y, Matsumae M：Chronic subdural hematoma in women. World Neurosurg 105：47-52, 2017

38) Hubbard RE, Rockwood K：Frailty in older women. Maturitas 69：203-207, 2011

39) Hughes JD, Samarage M, Burrows AM, Lanzino G, Rabinstein AA：Body mass index and aneurysmal subarachnoid hemorrhage：decreasing mortality with increasing body mass index. World Neurosurg 84：1598-1604, 2015

40) Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O'Brien J, Scheltens P, Visser MC, Wahlund LO, Waldermar G, Wallin A, Pantoni L；LADIS Study Group：Changes in white matter as determinant of global functional decline in older independent outpatients：three year follow-up of LADIS（leukoaraiosis and disability）study cohort. BMJ 339：b2477, 2009

41) Ishikawa E, Yanaka K, Sugimoto K, Ayuzawa S, Nose T：Reversible dementia in patients with chronic subdural hematomas. J Neurosurg 96：680-683, 2002

42) Iwamoto FM, Reiner AS, Panageas KS, Elkin EB, Abrey LE：Patterns of care in elderly glioblastoma patients. Ann Neurol 64：628-634, 2008

43) Joseph B, Pandit V, Zangbar B, Kulvatunyou N, Hashmi A, Green DJ, O'Keeffe T, Tang A, Vercruysse G, Fain MJ, Friese RS, Rhee P：Superiority of frailty over age in predicting outcomes among geriatric trauma patients：a prospective analysis. JAMA Surg 149：766-772, 2014

44) Kim BJ, Lee SH, Ryu WS, Kim CK, Lee J, Yoon BW：Paradoxical longevity in obese patients with intracerebral hemorrhage. Neurology 76：567-573, 2011

45) Kita D, Ciernik IF, Vaccarella S, Franceschi S, Kleihues P, Lütolf UM, Ohgaki H：Age as a predictive factor in glioblastomas：population-based study. Neuroepidemiology 33：17-22, 2009

46) 厚生労働省：健康日本21（第2次）の推進に関する参考資料（平成24年7月）

47) Kreisel SH, Blahak C, Bäzner H, Inzitari D, Pantoni L, Poggesi A, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O'Brien J, Scheltens P, Visser MC, Wahlund LO, Waldermar G, Wallin A, Hennerici MG：Deterioration of gait and balance over time：the effects of age-related white matter change--the LADIS Study. Cerebrovasc Dis 35：544-553, 2013

48) Leven DM, Lee NJ, Kothari P, Steinberger J, Guzman J, Skovrlj B, Shin JI, Caridi JM, Cho SK：Frailty index is a significant predictor of complications and mortality after surgery for adult spinal deformity. Spine（Phila Pa 1976）41：E1394-1401, 2016

49) Li J, Wang M, Won M, Shaw EG, Coughlin C, Curran WJ Jr, Mehta MP：Validation and simplification of the Radiation Therapy Oncology Group recursive partitioning analysis classification for glioblastoma. Int J Radiat Oncol Biol Phys 81：623-630, 2011

50) Luebke T, Brunkwall J：Meta-analysis and meta-regression analysis of the associations between sex and the operative outcomes of carotid endarterectomy. BMC Cardiovasc Disord 15：32, 2015

51) Mahmood K, Eldeirawi K, Wahidi MM：Association of gender with outcomes in critically ill patients. Crit Care 16：R92, 2012

52) Melin AA, Schmid KK, Lynch TG, Pipinos II, Kappes S, Longo GM, Gupta PK, Johanning JM：Preoperative frailty risk analysis index to stratify patients undergoing carotid endarterectomy. J Vasc Surg 61：683-689, 2015

53) Miller EK, Ailon T, Neuman BJ, Klineberg EO, Mundis GM Jr, Sciubba DM, Kebaish KM, Lafage V, Scheer JK, Smith JS, Hamilton DK, Bess S, Shaffrey CI, Ames CP；International Spine Study Group：Assessment of a novel adult cervical deformity frailty index as a component of preoperative risk stratification. World Neurosurg 109：e800-e806, 2018

54) Mitnitski AB, Mogilner AJ, Rockwood K：Accumulation of deficits as a proxy measure of aging. ScientificWorldJournal 1：323-336, 2001

55) Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, Sandercock P；International Subarachnoid Aneurysm Trial（ISAT）Collaborative Group：International subarachnoid aneurysm trial（ISAT）of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms：a randomized comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysms occlusion. Lancet 366：809-817, 2005

56) Mori K, Maeda M：Surgical treatment of chronic subdural hematoma in 500 consecutive cases：clinical characteristics, surgical outcome, complications, and recurrence rate. Neurol Med Chir（Tokyo）41：371-381, 2001

57) Mori K, Wada K, Otani N, Tomiyama A, Toyooka T, Fujii K, Kumagai K, Takeuchi S, Tomura S, Yamamoto T, Nakao Y, Arai H：Validation of effectiveness of keyhole clipping in nonfrail elderly patients with unruptured intracranial aneurysms. J Neurosurg 127：1307-1314, 2017

58) Morita A, Kirino T, Hashi K, Aoki N, Fukuhara S, Hashimoto N, Nakayama T, Sakai M, Teramoto A, Tominari S, Yoshimoto T；UCAS Japan Investigators：The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 366：2474-2482, 2012

59) Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB；American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2015 update：a report from the American Heart Association. Circulation 131：e29-e322, 2015

60) Newman WC, Neal DW, Hoh BL：A new comorbidities index for risk stratification for treatment of unruptured cerebral aneurysms. J Neurosurg 125：713-719, 2016

61) 日本脳卒中学会脳卒中ガイドライン委員会（編）：脳卒中治療ガイドライン2015．協和企画，東京，2015

62) 新阜宏文，松田昌之，半田譲二：老年者の慢性硬膜下血腫—統計的観察—．脳外誌4：359-363, 1995

63) 西　真理子，新開省二，吉田裕人，藤原佳典，深谷太郎，天野秀紀，小川貴志子，金　美芝，渡辺直紀：地域在宅高齢者における「虚弱（Frailty）」の疫学的特徴．日老医誌49：344-354, 2012

64) North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics, and progress. Stroke 22：711-720, 1991

65) 小川貴志子，藤原佳典，吉田裕人，西　真理子，深谷太郎，金　美芝，天野秀紀，李　相侖，渡辺直紀，新開省二：「基本チェックリスト」を用いた虚弱判定と虚弱高齢者の血液生化学・炎症マーカーの特徴．日老医誌48：545-552, 2011

66) O'Kelly CJ, Kulkarni AV, Austin PC, Wallace MC, Urbach D：The impact of therapeutic modality on outcomes following repair of ruptured intracranial aneurysms：an administrative data analysis. J Neurosurg 113：795-801, 2010

67) Quick J, Gessler F, Dützmann S, Hattingen E, Harter PN, Weise LM, Franz K, Seifert V, Senft C：Benefit of tumor resection for recurrent glioblastoma. J Neurooncol 117：365-372, 2014

68) Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, Fisher B, Fulton D, Gulavita S, Hao C, Husain S, Murtha A, Petruk K, Stewart D, Tai P, Urtasun R, Cairncross JG, Forsyth P：Abbreviated course of radiation therapy in older patients with glioblastoma multiforme：a prospective randomized clinical trial. J Clin Oncol 22：1583-1588, 2004

69) Roa W, Kepka L, Kumar N, Sinaika V, Matiello J, Lomidze D, Hentati D, Guedes de Castro D, Dyttus-Cebulok K, Drodge S, Ghosh S, Jeremić B, Rosenblatt E, Fidarova E：International Atomic Energy Agency randomized phase Ⅲ study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 33：4145-4150, 2015

70) Robinson TN, Wu DS, Pointer L, Dunn CL, Clevelanf JC Jr, Moss M：Simple frailty score predicts postoperative complications across surgical specialties. Am J Surg 206：544-550, 2013

71) Robinson TN, Wu DS, Sauaia A, Dunn CL, Stevens-Lapsley JE, Moss M, Stiegmann GV, Gajdos C, Cleveland JC Jr, Inouye SK：Slower walking speed forecasts increased postoperative morbidity and 1-year mortality across surgical specialties. Ann Surg 258：582-588, 2013

72) Rockwood K, Stadnyk K, MacKnight C, McDowell I, Hébert R, Hogan DB：A brief clinical instrument to classify frailty in elderly people. Lancet 353：205-206, 1999

73) Rockwood K, Song X, Mitnitski A：Changes in relative fitness and frailty across the adult lifespan；evidence from the Canadian National Population Heath Survey. CMAJ 183：E487-E494, 2011

74) Sarac TP, Hertzer NR, Mascha EJ, O'Hara PJ, Krajewski LP, Clair DG, Karafa MT, Ouriel K：Gender as a primary predictor of outcome after carotid endarterectomy. J Vasc Surg 35：748-753, 2002

75) Schuurmans H, Steverink N, Lindenberg S, Frieswijk N, Slaets JPJ：Old or frail：what tell us more? J Gerontol A Biol Sci Med Sci 59：M962-M965, 2004

76) Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, Fischbach AJ, Curran WJ Jr：Validation and predictive power of Radiation Therapy Oncology Group（RTOG）recursive partitioning analysis classes for malignant glioma patients：a report using RTOG 90-06. Int J Radiat Oncol Biol Phys 40：51-55, 1998

77) Shamliyan T, Talley KM, Ramakrishnan R, Kane RL：Association of frailty with survival：a systematic literature review. Aging Res Rev 12：719-736, 2013

78) Shi J, Yang Z, Song X, Yu P, Frang X, Tang Z, Peng D, Mitnitski A, Rockwood K：Sex differences in the limit to deficit accumulation in late middle-aged and older Chinese people：results from the Beijing Longitudinal Study of Aging. J Gerontol A Biol Sci Med Sci 69：702-709, 2014

79) Shibahara I, Watanabe T, Ezura M, Inoue T, Fujimura M, Kimura N, Inoue T, Sukzuki I, Nishino A, Nishimura S, Uenohara H, Tominaga T：Clinical features of subarachnoid hemorrhage in patients with positive cancer history. J Neurooncol 128：129-136, 2016

80) Shin JI, Kothari P, Phan K, Kim JS, Leven D, Lee NJ, Cho SK：Frailty Index as a predictor of adverse postoperative outcomes in patients undergoing cervical spinal fusion. Spine（Phila Pa 1976）42：304-310, 2017

81) Silver FL, Mackey A, Clark WM, Brooks W, Timaran CH, Chiu D, Goldstein LB, Meschia JF, Ferguson RD, Moore WS, Howard G, Brott TG；CREST Investigators：Safety of stenting and endarterectomy by symptomatic status in the Carotid Revascularization Endarterectomy Versus Stenting Trial（CREST). Stroke 42：675-680, 2011

82) Socha J, Kepka L, Ghosh S, Roa W, Kumar N, Sinaika V, Matiello J, Lomidze D, de Castro DG, Hentati D, Fidarova E：Outcome of treatment of recurrent glioblastoma multiforme in elderly and/or frail patients. J Neurooncol 126：493-498, 2016

83) Spangler EL, Goodney PP, Schanzer A, Stone DH, Schemerhorn ML, Powell RJ, Cronenwett JL, Nolan BW；Vascular Study Group of New England：Outcomes of carotid endarterectomy versus stenting in comparable medical risk patients. J Vasc Surg 60：1227-1231.e1, 2014

84) Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO；European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups；National Cancer Institute of Canada Clinical Trials Group：Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352：987-996, 2005

85) Syddall H, Cooper C, Martin F, Briggs R, Aihie Sayer A：Is grip strength a useful single marker of frailty? Age Ageing 32：650-656, 2003

86) Toi H, Kinoshita K, Hirai S, Takai H, Hara K, Matsushita N, Matsubara S, Otani M, Muramatsu K, Matsuda S, Fushimi K, Uno M：Present epidemiology of chronic subdural hematoma in Japan：analysis of 63, 358 cases recorded in a national administrative database. J Neurosurg 128：222-228, 2018

87) Tsiouris A, Hammoud ZT, Velanovich V, Hodari A, Borgi J, Rubinfeld I：A modified frailty index to assess morbidity and mortality after lobectomy. J Surg Res 183：40-46, 2013

88) van der Flier WM, van Straaten EC, Barkhof F, Verdelho A, Madureira S, Pantoni L, Inzitari D, Erkinjuntti T, Crisby M, Waldemar G, Schmidt R, Fazekas F, Scheltens P：Small vessel disease and general cognitive function in nondisabled elderly：the LADIS study. Stroke 36：2116-2120, 2005

89) van der Holst HM, van Uden IWM, Tuladhar AM, de Laat KF, van Norden AG, Norris DG, van Dijk EJ, Rutten-Jacobs LC, de Leeuw FE：Factors associated with 8-year mortality in older patients with cerebral small vessel disease：the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort（RUN DMC）Study. JAMA Neurol 73：402-409, 2016

90) Wallaert JB, Cronenwett JL, Bertges DJ, Schanzer A, Nolan BW, De Martino R, Eldrup-Jorgensen J, Goodney PP；Vascular Study Group of New England：Optimal selection of asymptomatic patients for carotid endarterectomy based on predicted 5-year survival. J Vasc Surg 58：112-118, 2013

91) Winovich DT, Longstreth WT Jr, Arnold AM, Varadhan R, Zeki Al Hazzouri A, Cushman M, Newman AB, Odden MC：Factors associated with ischemic stroke survival and recovery in older adults. Stroke 48：1818-1826, 2017

92) Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Mishkel GJ, Bajwa TK, Whitlow P, Strickman NE, Jaff MR, Popma JJ, Snead DB, Cutlip DE, Firth BG, Ouriel K；Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators：Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 351：1493-1501, 2004

93) Yagi M, Fujita N, Okada E, Tsuji O, Nagoshi N, Tsuji T, Asazuma T, Nakamura M, Matsumoto M, Watanabe K：Impact of frailty and comorbidities on surgical outcomes and complications in adult spinal disorders. Spine（Phila Pa 1976）43：1259-1267, 2018

94) Yue Q, Liu Y, Leng B, Xu B, Gu Y, Chen L, Zhu W, Mao Y：A prognostic model for early post-treatment outcome of elderly patients with aneurysmal subarachnoid hemorrhage. World Neurosurg 95：253-261, 2016