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1 CQ 1 1 10 ICD 10 /Alzheimer National Institute on Aging Alz heimer s Association workgroup NIA AA 5 DSM 5 ICD 10 1993 1 1 NIA AA 2011 Alzheimer 2 2 DSM 5 2013 neurocognitive disorders dementia major neurocognitive disorder DSM 5 6 1 1 ICD 10 1993 G1 1 2 1 2 G2 G1 G3 1 1 2 3 4 G4 G1 6 ICD 10 1993 2 1

1CQ 1 1 2 NIA AA 2011 1 2 3 4 1 2 5 2 a b c d e McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer s disease recommendations from the National Institute on Aging Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011 7 3 263 269. 3 DSM 5 DSM 5 2013 A 1 1 2 B C D DSM 5 2014 3 3 1 World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th Revision. Geneva World Health Organization 1993. 2 McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer s disease recommenda tions from the National Institute on Aging Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011 7 3 263 269. 3 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM 5. Arlington, VA American Psychiatric Association 2013. PubMed 2015 7 3 2015 8 8 #1 "Dementia/diagnosis" Majr OR "Dementia/classification" Majr OR dementia TI AND definition* TIAB OR criteria TIAB OR concept* TIAB OR "Cognition Disorders/diagnosis" Majr OR "Cognition Disorders/ classification" Majr OR cognition disorder* TI OR "cognitive dysfunction" TI AND definition* TIAB OR criteria TIAB OR concept* TIAB 2015 7 3 #1 /MTH OR /TI OR /MTH OR /TI AND SH,,, X,, OR /TH OR /TI AND /TI OR /TIOR /TI OR /TI OR /TI OR /TI OR /TI OR /TI OR /TI OR /TI 3

CQ 1 2 DSM 5 major neurocognitive disorder DSM 5 mild neurocognitive disorderdsm 5 subjective cognitive impairment SCI subjective cognitive decline SCD National Institute on Aging Alzheimer s Association workgroup NIA AAAlzheimer preclinical Alzheimer s disease 1 Alzheimer MCI due to Alzheimer s disease 2 Alzheimer Alzheimer s disease dementia Alzheimer 3 3 stage 1stage 2 stage 3 DSM 5 2013 neurocognitive disorders delirium major neurocognitive disorder DSM 5 mild neurocognitive disorderdsm 5 3 4 vascular cognitive impairment VCI vascular dementia VaD 5 VCI VaD cerebral autosomal dominant arteriop athy with subcortical infarcts and leukoencephalopathy CADASIL cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy CARASIL Binswanger Alzheimer VaD vascular cognitive disorder VCD 6 305 CQ14 1 2004 Petersen 7 DSM 5 NIA AA ICD 10 8 153 CQ4B 5 age associated memory impairment AAMIaging associated cognitive decline AACDmild cognitive disorder MCDmild neurocognitive decline MNCD cognitive impairment no dementia CIND 9 1 Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer s disease recommendations 4 1

1CQ 1 2 from the National Institute on Aging Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011 7 3 280 292. 2 Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer s disease recom mendations from the National Institute on Aging Alzheimer s Association workgroups on diagnostic guidelines for Alzhei mer s disease. Alzheimers Dement. 2011 7 3 270 279. 3 McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer s disease recommenda tions from the National Institute on Aging Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement. 2011 7 3 263 269. 4 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM 5. Arlington, VA American Psychiatric Association 2013. 5 Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006 37 9 2220 2241. 6 Roman GC, Sachdev P, Royall DR, et al. Vascular cognitive disorder a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci. 2004 226 1 2 81 87. 7 Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004 256 3 183 194. 8 World Health Organization. International Statistical Classification of Diseases and Related Health problems. 10th Revision. Geneva World Health Organization 1993. 9 2010 2010 PubMed 2015 7 3 2015 8 8 #1 "Dementia/diagnosis" Majr OR "Dementia/classification" Majr OR dementia TI AND definition* TIAB OR criteria TIAB OR concept* TIAB OR "Cognition Disorders/diagnosis" Majr OR "Cognition Disorders/ classification" Majr OR cognition disorder* TI OR "cognitive dysfunction" TI AND definition* TIAB OR criteria TIAB OR concept* TIAB 2015 7 3 #1 /MTH OR /TI OR /MTH OR /TI AND SH,,, X,, OR /TH OR /TI AND /TI OR /TIOR /TI OR /TI OR /TI OR /TI OR /TI OR /TI OR /TI OR /TI 5

CQ 1 3 DSM 5 Alzheimer Lewy HIV Parkinson Huntington 1 1 ICD 10 Alzheimer 2 DSM 5 Alzheimer Lewy HIV Parkinson Huntington 3 B 12 treatable dementia 1 2010 2010 4 7 2 World Health Organization. International Statistical Classification of Diseases and Related Health problems. 10th Revision. Geneva World Health Organization 1993. 3 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM 5. Arlington, VA American Psychiatric Association 2013. PubMed 2015 7 3 #1 "Dementia/etiology" Majr OR dementia TI AND etiology OR "Cognition Disorders/etiology" Majr OR cognition disorder* TI OR "cognitive dysfunction" TI AND etiology AND "Risk Factors" Majr OR risk factor* TI 2015 7 3 #1 /MTH OR /TI OR /MTH OR /TI AND SHOR /TI or /TI 6 1

1CQ 1 3 1 1 Alzheimer Lewy /Parkinson Huntington 2VaD VaD VaD VaD 3 4 5 6 7 HIV AIDS Creutzfeldt Jakob 8 9 Cushing 10 Marchiafava Bignami B 1 Wernicke Korsakoff B 12 D A 5 FU B C D Wilson 11 Behçet Sjögren 12 13 Fahr AND /TH OR /TI OR /TI AND PT OR SHAND /TI or / TI 7

CQ 1 4 Alzheimer DSM 5 1 Alzheimer 1 3 1. 1 2. 2 3. 3 Alzheimer 4. 18 5. 2 8 1

1CQ 1 4 1Alzheimer Alzheimer 2 Alzheimer Alzheimer 3 Alzheimer Alzheimer 1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM 5. Arlington, VA American Psychiatric Association 2013. 2 2010 2010 PubMed 2015 7 3 #1 "Dementia/diagnosis" Majr OR dementia TI AND diagnosis OR diagnostic OR "Cognition Disorders/ diagnosis" Majr OR cognition disorder* TI OR "cognitive dysfunction" TIAND diagnosis OR diagnostic AND "Diagnosis, Differential" Majr OR "Diagnostic Errors" Mesh OR "differential diagnosis" TI OR diagnostic error* TI OR misdiagnosis TI 2015 7 3 #1 /MTH OR /TI OR /MTH OR /TI AND SH,,, X,, OR /TH OR /TI AND /MTH OR /TI OR /MTH OR /TI OR /TI 9

CQ 1 5 2010 65 15% A 1980 2000 65 3.8 11% 1 8 2012 462 15% 1 2,3 2012 2025 675 95% CI 541 844 20% 2025 730 95%CI 570 936 4 2015 4,680 20 2030 7,470 2050 1 3,150 2 5 6 7 10 [%] 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 65~69 70~74 75~79 80~84 85~89 90~94 95~[ 歳 ] 男性女性全体 1 2012 23 24 2013 10 1

1CQ 1 5 [100 万人 ] 150 100 89.28 77.63 66.45 50 56.16 27.28 32.30 38.72 46.74 19.50 21.97 24.73 27.95 31.72 35.71 39.14 42.18 0 2015 2020 2025 2030 2035 2040 2045 2050[ 年 ] 2 Alzheimer s Disease International. World Alzheimer Report 2015 The Global Impact of Dementia an analysis of prevalence, incidence, cost and trends. London Alzheimer s Disease International 2015. 高所得国 低 ~ 中所得国 1 Dodge HH, Buracchio TJ, Fisher GG, et al. Trends in the prevalence of dementia in Japan. Int J Alzheimers Dis. 2012 2012 956354. 2 Ikejima C, Hisanaga A, Meguro K, et al. Multicentre population based dementia prevalence survey in Japan a preliminary report. Psychogeriatrics. 2012 12 2 120 123. 3 23 24 2013 4 26 2015 5 Alzheimer s Disease International. World Alzheimer Report 2015 The Global Impact of Dementia an analysis of preva lence, incidence, cost and trends. London Alzheimer s Disease International 2015. 6 Matthews FE, Arthur A, Barnes LE, et al. A two decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England results of the Cognitive Function and Ageing Study I and II. Lancet. 2013 382 9902 1405 1412. 7 Qiu C, von Strauss E, Bäckman L, et al. Twenty year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden. Neurology. 2013 80 20 1888 1894. 8 Schrijvers EM, Verhaaren BF, Koudstaal PJ, et al. Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology. 2012 78 19 1456 1463. 9 Doblhammer G, Fink A, Fritze T. Short term trends in dementia prevalence in Germany between the years 2007 and 2009. Alzheimers Dement. 2015 11 3 291 299. 10 Satizabal CL, Beiser A, Chêne G, et al. Temporal trends in Dementia Incidence in the Framingham Study. 2014 Jul 17 Copenhagen AAIC 2014. PubMed 2015 5 28 2015 10 19 #1 "Dementia/epidemiology" Majr OR dementia TIAND "Morbidity" Mesh OR morbidity TI OR incidence TI OR prevalence TI 2015 5 28 #1 /TH OR /TI AND /TH OR /TI OR /TI AND /TH OR /TI OR / TI OR /TI 11

CQ 1 6 Alzheimer B 2010 Alzheimer 67.6% 19.5% Lewy / Parkinson 4.3% 1 1980 Alzheimer 1990 Alzheimer 80 2 Alzheimer 1 3 5 Alzheimer 6 Lewy 1 Alzheimer % % % 65 1980 4.4 1.9 2.0 1 1990 4.5 2.5 1.7 2000 5.9 3.6 2.2 65 1985 6.0 1.1 2.3 2 1992 4.4 1.3 1.5 1998 5.3 2.3 1.5 2005 8.3 3.8 2.5 65 1985 4.9 2.8 1.8 3 1990 5.4 2.4 2.0 1996 5.7 2.5 2.7 2001 7.0 3.3 2.4 1 1980 2 1985 3 1985 12 1

1CQ 1 6 1 23 24 2013 2 Dodge HH, Buracchio TJ, Fisher GG, et al. Trends in the prevalence of dementia in Japan. Int J Alzheimers Dis. 2012 2012 956354. 3 Wakutani Y, Kusumi M, Wada K, et al. Longitudinal changes in the prevalence of dementia in a Japanese rural area. Psychogeriatrics. 2007 7 4 150 154. 4 Sekita A, Ninomiya T, Tanizaki Y, et al. Trends in prevalence of Alzheimer s disease and vascular dementia in a Japanese community the Hisayama Study. Acta Psychiatr Scand. 2010 122 4 319 325. 5 2003 14 12 1509 1518 6 26 2015 PubMed 2015 5 28 #1 "Dementia/epidemiology" Majr OR dementia TIAND "Morbidity" Mesh OR morbidity TI OR incidence TI OR prevalence TIAND subtype TI OR subtypes TI OR "sub type" TI OR "sub types" TI 2015 5 28 #1 /TH OR /TI AND /TH OR /TI OR /TI OR /TI AND /AL 13

CQ 1 7 C 1990 2000 10 37% 1 70 HR 1993 2.53 2002 3.11 9 p 0.09 2 1988 2002 14 29% HR 1988 2.42 2002 2.47 12 3 2,3 2004 2007 3 1% p 0.75 11% p 0.001 4 [%] 100 90 80 70 60 50 40 30 20 10 0 1980 1985 1990 1995 2000 2005 2010 2015[ 年 ] 知症者の平均余命の喪失報告年認 1 % Brodaty H, Seeher K, Gibson L. Dementia time to death a systematic litera ture review on survival time and years of life lost in people with dementia. Int Psychogeriatr. 2012 24 7 1034 1045. 14 1

1CQ 1 7 %1980 90 1 5 1 Schrijvers EM, Verhaaren BF, Koudstaal PJ, et al. Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology. 2012 78 19 1456 1463. 2 Langa KM, Larson EB, Karlawish JH, et al. Trends in the prevalence and mortality of cognitive impairment in the United States is there evidence of a compression of cognitive morbidity? Alzheimers Dement. 2008 4 2 134 144. 3 Qiu C, von Strauss E, Bäckman L, et al. Twenty year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden. Neurology. 2013 80 20 1888 1894. 4 Doblhammer G, Fink A, Fritze T. Short term trends in dementia prevalence in Germany between the years 2007 and 2009. Alzheimers Dement. 2015 11 3 291 299. 5 Brodaty H, Seeher K, Gibson L. Dementia time to death a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr. 2012 24 7 1034 1045. PubMed 2015 10 19 #1 "Dementia/mortality" Majr OR "Cognition Disorders/mortality" Majr OR "Dementia/epidemiology" Majr OR "Cognition Disorders/epidemiology" Majr AND "Mortality" Mesh OR mortality TIAB OR survival TIABAND "Morbidity" Mesh OR "Life Expectancy" Mesh OR "morbidity" TI OR "incidence" TI OR "prevalence" TI OR "disease duration" TI OR "dementia" TI AND "morbidity" TI OR "incidence" TI OR "prevalence" TI 2015 10 19 #1 /MTH OR /TI OR /MTH OR /TI AND /TI OR /TH OR / TI OR /TI OR /TH OR /TH OR /TI OR /TI OR /TI 15

CQ 1 8 Alzheimer β(aβ) 1 Alzheimer Lewy α Lewy Lewy 2 Parkinson Lewy Lewy Alzheimer 3 Pick fronto temporal lobar degeneration FTLD TDP 43 fused in sarcoma FUS 4 Pick Pick TDP 43 FTLD FTLD 80 90 Aβ Alzheimer primary age related tauopathy PART 5 CA1 Alzheimer FTLD 16 1

1CQ 1 8 6 chronic traumatic encephalopathy CTE 7 8 Alzheimer Alzheimer 314 CQ14 4 1 Braak H, Braak E. Neuropathological staging of Alzheimer related changes. Acta Neuropathol. 1991 82 4 239 259. 2 Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson s disease. Neurobiol Aging. 2003 24 2 197 211. 3 McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies third report of the DLB Consortium. Neurology. 2005 65 12 1863 1872. 4 Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration an update. Acta Neuropathol. 2010 119 1 1 4. 5 Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age related tauopathy PART a common pathology associated with human aging. Acta Neuropathol. 2014 128 6 755 766. 6 Brenowitz WD, Monsell SE, Schmitt FA, et al. Hippocampal sclerosis of aging is a key Alzheimer s disease mimic clini cal pathologic correlations and comparisons with both alzheimer s disease and non tauopathic frontotemporal lobar degeneration. J Alzheimers Dis. 2014 39 3 691 702. 7 McKee AC, Daneshvar DH, Alvarez VE, et al. The neuropathology of sport. Acta Neuropathol. 2014 127 1 29 51. 8 Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia an update. Nat Rev Neurol. 2015 11 3 157 165. PubMed 2015 7 24 #1 "Dementia/pathology" Majr OR dementia TI AND patholog* TI OR neuropatholog* TIAND "Brain/ pathology" Majr OR "Parkinson Disease/pathology" Majr OR "Inclusion Bodies/metabolism" Mesh AND neuropathologic TI OR neuropathological TI OR pathologic TI OR "Frontotemporal Lobar Degeneration/ pathology" Mesh OR "Lewy Body Disease/pathology" Mesh OR "Alzheimer Disease/pathology" Majr OR Alzheimer* TI AND patholog* OR neuropatholog* AND "Brain/pathology" Mesh OR "Parkinson Disease/ pathology" Mesh OR "primary age related tauopathy" TIAB OR PART TI AND "pathological feature" TIAB OR "pathological process" TIAB OR "pathologic process" TIAB OR "neuropathological criteria" TIAB OR neuropathological stage* TIAB OR pathogenic mechanism* TIAB OR "Frontotemporal Lobar Degeneration/classification" Majr OR "Lewy Body Disease/physiopathology" Majr OR "Tauopathies/pathology" Majr AND "Aging/pathology" MajrOR "Athletic Injuries/pathology" Majr AND Cognition Mesh AND "Brain/pathology" Majr OR "Inclusion Bodies/metabolism" Mesh AND neuropatholog* TI OR patholog* TI OR "pathologic assessment" TIAB 2015 7 24 #1 /TH OR /TI OR Alzheimer/TI OR /TI OR Lewy /TI AND /TH OR /TI OR Parkinson /TH OR Parkinson/TI AND SH OR /TH AND /TI AND /TI OR /TI OR Alzheimer/TI OR /TI OR Lewy /TI 17