臨床神経学雑誌第49巻第5号
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1 Alzheimers β
2 Table1 NeuropathologicalclassificationofFTLD 1.Tauopathy(withassociatedneuronlossandgliosis)andinsolubletauwithapredominanceof3Rtau,themostlikely diagnosesare: FTLD withpickbodies a) FTLD withmapt mutation 2.Tauopathy(withassociatedneuronlossandgliosis)andinsolubletauwithapredominanceof4Rtau,themostlikely diagnosesare: Corticobasaldegeneration(CBD) Progressivesupranuclearpalsy(PSP) Argyrophilicgraindisease(AGD) Sporadicmultiplesystem tauopathywithdementia FTLD withmapt mutation 3.Tauopathy(withassociatedneuronlossandgliosis)andinsolubletau,withapredominanceof3Rand4Rtau,themost likelydiagnosesare: Neurofibrilarytangledementia FTLD withmapt mutation 4.Frontotemporalneuronallossandgliosiswithouttau-orubiquitin/P62-positiveinclusions,themostlikelydiagnosisis: FTLD (alsoknownasdementialackingdistinctivehistologicfeatures:dldh) 5.TDP-43proteinopathywithassociatedneuronallossandubiquitin-positive/P62-positive,tau-negativeinclusions,with MND orwithoutmnd butwithmnd-typeinclusions,themostlikelydiagnosesare: FTLD-U withmnd (FTLD-U types1-3) FTLD-U butwithoutmnd (FTLD-U types1-3) b) FTLD-U withpgrn mutation(ftld-u type3) FTLD-U withvcpmutation(ftld-u type4) FTLD-U linkedtochromosome9p(ftld-u type2) OtherasyetunidentifiedTDP-43proteinopathies 6.Frontotemporalneuronallossandgliosiswithubiquitin-positive/P62-positive,TDP-43-andtau-negativeinclusions, themostlikelydiagnosesare: FTLD-U withchmp2bmutation Basophilicinclusionbodydisease(BIBD) OtherasyetunidentifiedFTLD-U,non-TDP-43proteinopathies 7.Frontotemporalneuronallossandgliosiswithubiquitin/P62andα-internexin-positiveinclusions,themostlikelydiagnosisis: Neuronalintermediatefilamentinclusiondisease(NIFID) a) Pick sdiseasecasescorrespondtoftld withpickbodies. b) SporadicFTLD-TDP casesinthispapercorrespondto FTLD-U butwithoutmnd.chmp2bchargedmultivesicularbodyprotein2bgene,ftld frontotemporallobardegeneration,ftld-u FTLD withubiquitin-positive,tau-,α-synuclein-,tdp-43-,andneuronalintermediatefilamentproteinnegativeinclusions,mapt microtubule-associatedproteintaugene,mnd motorneurondisease,neurofibrilarytangle dementia,alsocaledtanglepredominantform ofseniledementia,pgrn progranulingene,tdp-43tardna-binding protein43,vcpvalosin-containingproteingene,dntc difuseneurofibrilarytangleswithcalcification,sd-nft Senile dementiaoftheneurofibrilarytangletype.reprintedwithpermissionfrom Ref. 6). α
3 Fig.1 PathologicalhalmarksofPick sdiseaseandftld-tdp. (a)pickbodiesinthetemporalcortex.(b)type1histologyofftld-tdp.relativelythickandlong TDP-43-positivedystrophicneuriteswithfew ornoneuronalinclusionsareseen.thetemporal cortex.(c)type2histologyofftld-tdp.manytdp-43-positiveintracytoplasmicinclusionswith few ornodystrophicneuritesarevisible.thetemporalcortexinacaseofalswithdementia.(d) Type3histologyofFTLD-TDP.Bothmanyshortdystrophicneuritesandintracytoplasmicinclusionsarenoted.Thetemporalcortex. (a)tauimmunohistochemistry,(b-d)phosphorylatedtdp-43immunohistochemistry.(a)scalebars= (a)50μm and(b-d)100μm.
4 Table2 NomenclatureforneuropathologicsubtypesofFTLD Currentterminology Tau-positiveFTLD Tau-negativeFTLD FTLD-U TDP-43-positive TDP-43-negative Neuronalintermediatefilament inclusiondisease(nifid) Dementialackingdistinctive histopathology(dldh) Other Basophilicinclusion bodydisease(bibd) Recommended new terminology FTLD-tau FTLD-TDP FTLD-UPS FTLD-IF FTLD-ni BIBD Majorpathologicalsubtypes Pick sdisease Corticobasaldegeneration Progressivesupranuclearpalsy Argyrophilicgraindisease Multiplesystem tauopathywithdementia Unclassifiable Type1-4 Unclassifiable atypicalftld-u FTD linkedtochromosome3 Reprintedwithpermissionfrom Ref. 9).
5 Table3 DemographicdataofPick sdisease,ftld-tdp,andftld-mnd cases Pick s disease A l FTLD-TDP FTLD-TDP- PLS(+ ) FTLD-TDP FTLD-TDP- PLS(- ) FTLD-TDP- PLS(ne) FTLD-MND N (male/female) Ageatonset(y) Ageatdeath(y) Duration(y) Familyhistory(n) Brainweight(g) TDP-43pathology Type1[n(%)] Type2[n(%)] Type3[n(%)] Type4[n(%)] 19(9/10) 55.9± ± ± ,012± (14/6) 54.5± ± ± ,049± (55.0) 5(25.0) 4(20.0) 14(10/4) 52.9± ± ± ,016± 189 8(57.1) 3(21.4) 3(21.4) 4(3/1) 62.7± ± ± ,170± 314 2(50.0) 1(25.0) 1(25.0) 2(1/1) 52.0± ± ± ,150 a) 1(50.0) 1(50.0) 9(2/7) 63.6± ± ± ,251± 105 9(100.0) Theageatonset,ageatdeath,duration,andbrainweightweremean± standarddeviation. FTLD-TDP-PLS(+),FTLD-TDPwithPLS-likecorticospinaltractdegeneration; FTLD-TDP-PLS(-),FTLD-TDPwithoutPLS-likecorticospinaltractdegeneration; FTLD-TDP-PLS(ne),FTLD-TDPcasesofwhichmedulaoblongataorspinalcordtissuecouldnotbehistopathologicaly examined ạ ) ThebrainweightinonecaseofFTLD-TDP-PLS(ne)wasnotavailable.Reprintedwithpermissionfrom Ref. 23). χ
6 臨床神経学 49巻５号 2009 ５ 錐体路徴候は FTLD-TDP-PLS のみでみとめた FTLDTDP-PLS でも左右差のあるパーキンソニズムを 67 に みとめた 発症から左右差のある運動障害出現まで平均 6 年 その後死亡までは平均 2.5 年であった 2-4 半側空間無視 FTLD の頭頂葉症状はほとんど注目されていない 半側空 間無視は左右差のある運動障害を呈 し た FTLD-TDP-PLS かったが 1 例 5 で肢節運動失行をみとめた 3 FTLD 症候群の展開パターン Table 5 FTLD 患者は通常 FTD SD PA の幾つかを順に呈す そ の展開パターンは組織変性の進展を反映するはずである わ れわれの検討では Pick 病と FTLD-TDP の症候群の展開パ ターンにはそれぞれ規則性があり 互いにほとんど重複しな かった 14 例中 2 例 14 に記載があり 運動障害と同側に出 Pick 病でもっとも多い最初の症候群 第一症候群 は FTD 現した これは 患側の反対側をいつも見ている 患側から近 64 次いで PA か発語失行 計 21 であった 経過中 づくと認識しない 麻痺は無いにもかかわらず患側上肢をも FTD のみに終始する FTD 単独型 脱抑制や常同の行動障害 ちいない事などで気付かれた Pick 病に半側無視の記載はな で発症し SD や PA や非対称性の運動障害を呈さずしだいに
7 Table5 EvolvingpaternsofclinicalpresentationinFTLD-TDPandPick sdiseasegroups Clinicalcourse Pick sdisease (n= 14) FTLD-TDP (n= 18) (1)Schizophrenia(subclinicalFTLD) (2)AOS> AMD (rt) (3)PA (4)PA> FTD (5)Delusionalstate> FTD > AMD (lt) (6)FTD > IAC (7)FTD (8)FTD (9)FTD (10)FTD (11)FTD (12)FTD (13)FTD (14)FTD (15)FTD > AMD (lt) (16)FTD > SD> AMD (rt) (17)FTD > IAC> AMD (lt)>sa (lt) (18)FTD > IAC> AMD (rt)>sa (rt) (19)Delusionalstate> IAC> FTD> AMD (lt) (20)Gaitdisturbance>FTD > AMD (lt) (21)Memoryimpairment>FTD > AMD (lt) (22)Memoryimpairment>AMD(rt) (23)IAC> FTD > AMD (rt) (24)IAC> FTD > AMD (lt) (25)SD> AMD (rt) (26)SD (27)SD> FTD (28)SD> FTD (29)SD> FTD > AMD (rt) (30)SD> FTD > AMD (rt) (31)SD> FTD > AMD (rt) Cerebral atrophy None F> Tlt F> Tlt Flt= T T> Frt Frt= T F= T F= T F> Trt F> T F Clinicaldiagnosis (yearofdeath) Schizophrenia(1981) PPApraxia(1994) PPAphasia(n.a.) Pick(1971) Preseniledem.(1993) Pick(1964) Preseniledem.(1993) Pick(1983) Pick(1974) n.a. Pick(1995) Pick(1968) AD (1976) Depressivestate(1992) TDP-43 subtype a 3 a b 1 b 1 1 a Cerebral atrophy F c T> F F= T T= F T> F Trt F= Tlt Flt= T F> Tlt Tlt T> F T> F T> F Clinicaldiagnosis (yearofdeath) AD (2000) Pick(1988) Pick(2003) Pick(1979) SD?(1995) Pick(1973) Pick(1986) Pick(1974) CBD (2006) VaD (1977) Pick(1975) SPA (1998) Pick(1985) Pick(1983) VaD (1991) SPA (2000) Pick(2000) Pick(1974) OneFTLD-TDP-PLS(+)case,oneFTLD-TDP-PLS(-)case,andfivePick sdiseasecaseswereexcludedbecausetheclinical informationwasnotadequate.thepercentagesof18ftld-tdpand14pick sdiseasecasesforwhichclinicalinformation wasavailable,respectively,areindicated.t> F,temporal-predominantatrophy;F> T,frontal-predominantatrophy;T= F, temporalandfrontallobeswereequalyatrophic;lt,leftside-predominantatrophy;rt,rightside-predominantatrophy.a) FTLD-TDP-PLS(-)cases.b)FTLD-TDP-PLS(ne)cases.TheothercasesofFTLD-TDPwereFTLD-TDP-PLS(+).c)Microscopicaly,thefrontalandtemporalcorticeswereequalydegenerated.FTD,frontotemporaldementia;SD,semanticdementia;PA,progressivenon-fluentaphasia;AOS,apraxiaofspeech;IAC,impairmentofauditorycomprehension;AMD (rt),right side-predominantasymmetricmotordisturbance;amd (lt),leftside-predominantasymmetricmotordisturbance;sa,unilateralspatialagnosia;spa,slowlyprogressiveaphasia;ppaphasia,primaryprogressiveaphasia;ppapraxia,primaryprogressiveapraxia;pick,pick sdisease;ad,alzheimer sdisease;cbd,corticobasaldegeneration;vad,vasculardementia;sd,standarddeviation;n.a.,notavailable.reprintedwithpermissionfrom Ref. 23).
8 Fig.2 DistributionofneuronallossinPick sdiseaseandsporadicftd-tdp. NeuronallossinthefrontalcortexinPick sdiseaseismoreseverethanthatinsporadicftld-tdp, whileneuronallossinthetemporalcortexinsporadicftld-tdpismoreseverethanthatinpick s disease.degenerationinthesuperiortemporalgyrus,caudatenucleus,putamen,globuspalidus,substantianigra,andcorticospinaltract(cst)insporadicftld-tdpissignificantlymoreseverethan thatinpick sdisease.reprintedwithpermissionfrom Ref. 23).
9 Fig.3 CoronalsectionsatthelevelofthenucleusaccumbensoramygdalainPick sdiseasecases. Casesareshowninorderofdiseaseduration.Theupperlayer:Klüver-Barrera(KB)stain(myelin stain);thelowerlayer:holzerstaindemonstratingfibrilarygliosis.(a,b)a casewithadiseasedurationof1.5years.gliosisisfoundonlyinthefrontalconvexity(arrow).thewidthofthecorticalribbon inthesiteisnarrowerthanthatinthesurroundings.(c,d)thesamecaseshownin(a,b).noremarkablechangeexceptforslightgliosisintheamygdalaisnotedinthefrontalandtemporalcortices. Thispatientinitialyshowedreductionofuteranceandapathy,anddiedsuddenlyafteradmission. Nobehavioralproblem wasnoticed.(e,f)a casewithadurationof7years.thewidthofthecortical ribbonintheinferiorfrontalgyrusisseverelyreduced,andgliosisinthesiteisalsoremarkable (arrows).thissitecorrespondstotheparsopercularis.incontrast,thetemporalcortexappearstobe relativelywelspared.subcorticalgliosisinthefrontallobeismoreseverethanthatinthetemporal lobe.thispatientfirstshowedftd,andsubsequentlyimpairmentofspeechoutputwasnoted.(g,h) A casewithadurationof8years.thiscasealsohadseverecorticalatrophyandgliosisintheinferiorfrontalgyrus(arrows).subcorticalgliosisinthefrontallobeismoreseverethanthatinthetemporallobe.thefirstsyndromeofthispatientwasapraxiaofspeech,whilenobehavioraldisturbance wasnoticedduringthecourse.(i,j)a casewithadurationof12years.inthiscasealso,themostseverelyafectedistheinferiorfrontalgyrus(arrows).thispatientinitialydevelopedimpairmentof speechoutput.later,limbapraxiaandideomotorapraxiaoccurred.itisnoteworthythatinalpick s diseasecasespresentedhere,theatrophyofthebasalgangliawasmildandaseverereductionof theirvolume,asevidencedbyaconcavityoftheventricularsurface,wasnotnoted.
10 Fig.4 CoronalsectionsatthelevelofthenucleusaccumbensoramygdalainsporadicFTLD-TDP cases. Casesareshowninorderofdiseaseduration.Theupperlayer:Klüver-Barrera(KB)stain(myelin stain);thelowerlayer:holzerstain,whichrevealsfibrilarygliosis.(a,b)a casewithadiseasedurationof9.5years.lossofmyelinandmildgliosisarefoundinthetemporallobe(arrows),whilethe frontallobeappearstobespared.thecaudatenucleusisslightlyatrophic,butitsstructureisnot flatened.thispatientinitialydevelopedimpairmentofsemanticmemory,anddisinhibitedbehaviorsbegantwoyearslater.nineyearsaftertheonset,tremor,rigidity,contracture,andbabinski signintherightsideextremitiesdeveloped.(c,d)a casewithadurationof11years.incontrastto therelativelypreservedfrontallobe,severelossofmyelinandgliosisisnotedinthetemporallobe (arrows).thestructureofthecaudatenucleusisflatened.theinitialsymptomsofthiscasewere irritabilityandapathy.tenyearsaftertheonset,clumsinessintheleft-sideextremitiesalso developed.(e,f)a casewithadurationof12years.severecorticalatrophywithsubcorticalgliosis wasnotedinthetemporallobe,andtoalesserdegree,inthefrontallobealso(longarrows).the caudatenucleusismildlyconcave(shortarrow).thiscaseinitialyshowedreduceduteranceand impairedrecognitionoffriends'facesandcommonobjects,anddevelopedstereotypicbehaviors6 yearslater.(g,h)a casewithadurationof13years.severetemporaldegenerationandmilderfrontalatrophyarefound.thefirstsyndromeofthispatientwassemanticdementia.(i,j)a casewith adurationof21years.althoughboththetemporalandfrontallobesareseverelydegenerated (longarrows),subcorticalgliosisandthereductionofthewidthofthecorticalribbonarethemost remarkableinthetemporallobe.thebasalgangliashow remarkablereductionofvolume,whichis evidencedbyanovertconcavityoftheventricularsurface(shortarrow).thispatientinitialy showeddelusionalstate,andsubsequently,impairedcomprehension,disinhibitedbehaviors,and oraltendencyoccurred.sixyearsaftertheonset,babinskisign,increaseddeeptendonreflex,and contractureintherightsideextremitieswereobserved.
11 Fig.5 Distributionofneuronallossinfrontalandtemporal corticesinpick sdiseaseandsporadicftld-tdpbydiseaseduration.inapick sdiseasegroupwithadiseasedurationof5yearsorless,temporal-predominantcasesand frontal-predominantcasesareincluded,butnocasehad equaldegenerationinthefrontalandtemporalcortices.in apick sdiseasegroupwithadurationof11yearsormore, however,thefrontalandtemporalcorticesareequalydegeneratedin50% ofcases.incontrast,insporadicftld- TDP,thetemporalcortexisconsistentlymoredegenerated than thefrontalcortex regardlessofthedisease duration.f< T,temporal-predominantneuronalloss;F= T,equaldegenerationinthefrontalandtemporalcortices; F> T,frontal-predominantneuronalloss. Fig.6 Severityofmacroscopicatrophyinbasalgangliain Pick s disease and sporadic FTLD-TDP by disease duration.inapick sdiseasegroupwithadiseaseduration of5yearsorless,nocaseshowsaflatenedstructureof thecaudatenucleus.likewise,inapick sdiseasegroup withadurationof6to10years,only15% casesshow slightconcavity.incontrast,about35% ofsporadicftld- TDPcaseswithadiseasedurationof5yearsorlessshow theflatenedcaudatenucleus,and50% ofsporadicftld- TDPcaseswithadurationof6to10yearsexhibitconcavityofthecaudatenucleus.
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研修コーナー
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臨床神経学雑誌第48巻第1号
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ISSN 0386-7617 Annual Research Reports No.33, 2009 THE FOUNDATION FOR GROWTH SCIENCE ön é
