Tib neeg-Specific Contributions Of Brain Pathologies To Progressive Parkinsonism in Older Adults
Jul 21, 2023
Abstract
Keeb kwm: Mixed-brain pathologies yog feem ntau ua rau kev loj hlob parkinsonism hauv cov laus. Peb tau sim qhov kev xav tias qhov cuam tshuam ntawm tus kheej pathologies cuam tshuam nrog kev loj hlob parkinsonism txawv ntawm cov neeg laus. Cov txheej txheem: Cov ntaub ntawv yog los ntawm 1089 tus neeg txiav txim siab uas tau ua tiav kev kuaj mob txhua xyoo thiab kev kuaj mob hauv lub cev. Parkinsonism yog raws li kev hloov kho United Parkinson's Disease Rating Scale. Cov qauv sib xyaw ua ke tau ua haujlwm, los tshawb xyuas qhov sib xyaw ua ke ntawm 9 pathologies ntsig txog kev nce qib parkinsonism. Tom qab ntawd peb kwv yees tus neeg tshwj xeeb kev koom tes ntawm txhua tus kab mob rau kev loj hlob parkinsonism. Cov txiaj ntsig: Cov neeg koom nrog nruab nrab pom 3 kab mob. Parkinson's disease (PD) thiab 4 cerebrovascular pathologies (microinfarcts, atherosclerosis, arteriolosclerosis, thiab cerebral amyloid angiopathy [CAA]), tab sis tsis yog Alzheimer's kab mob, TDP-43, hippocampal sclerosis, thiab microinfarcts kev vam meej. Cov pathologies suav txog 13 feem pua ntawm qhov sib txawv ntxiv ntawm kev nce qib parkinsonism. Peb caug-ib qhov sib txawv ntawm cov 5 pathologies tau pom tias muaj feem cuam tshuam nrog kev nce qib parkinsonism pom. Qhov nruab nrab, PD thiab CAA suav nrog, feem, rau 66 feem pua thiab 65 feem pua ntawm cov tib neeg tshwj xeeb kev loj hlob ntawm tus neeg mob Parkinsonism, thaum macroinfacts, atherosclerosis, thiab arteriolosclerosis suav txog 41 feem pua -48 feem pua. Xaus: Muaj ntau qhov sib txawv ntawm qhov sib txawv thiab cov txheeb ze cuam tshuam ntawm ib tus neeg lub hlwb pathologies cuam tshuam txog kev loj hlob parkinsonism dua li yav dhau los lees paub thiab qhov no yuav suav nrog ib feem rau nws cov phenotypic heterogeneity hauv cov neeg laus.
Cov teebmeem ntawm Cistanche-Anti Parkinson tus kab mob
Nyem qhov no mus saib Cistanche cov khoom
【Nug ntxiv】 Email: cindy.xue@wecistanche.com / Whats App: 0086 18599088692 / Wechat: 18599088692
Cov lus tseem ceeb: Kev laus, Lub hlwb pathology, Kev paub tsis meej, Parkinsonism
Cov kab mob sib xyaw ua ke hauv hlwb uas sib sau ua ke hauv cov hlwb laus feem ntau cuam tshuam nrog kev loj hlob ntawm Parkinsonism thiab lub nra hnyav dua ntawm cov kab mob no ua rau muaj kev pheej hmoo ntawm kev loj hlob parkinsonism (1-5). Txawm li cas los xij, tus neeg tshwj xeeb cuam tshuam ntawm tus kheej pathologies ntawm kev loj hlob parkinsonism tsis paub. Hauv ib txoj kev tshawb fawb tsis ntev los no, peb tau siv cov kev tshuaj ntsuam xyuas tshiab los txheeb xyuas qhov cuam tshuam ntawm tus neeg tshwj xeeb ntawm tus kheej cov kab mob uas ua rau muaj kev xav tsis zoo (6). Txoj kev tshawb no tom kawg tau tsom tshwj xeeb rau kev paub txog kev poob qis thiab tsis tau tshuaj xyuas cov kev mob Parkinsonism (6). Txoj kev tshawb no tau sim qhov kev xav tias tus neeg tshwj xeeb cuam tshuam ntawm tus kheej pathologies cuam tshuam nrog tus nqi ntawm kev nce qib par parkinsonism txawv ntawm cov neeg laus. Txhawm rau ntsuas qhov kev xav no, peb siv cov ntaub ntawv kho mob thiab tom qab tuag los ntawm 1089 tus neeg txiav txim siab uas tau koom nrog 3 cov kev tshawb fawb hauv zej zog thiab pom zoo rau kev txiav txim siab ntawm lub sijhawm tuag los txiav txim siab txog tus neeg tshwj xeeb cuam tshuam ntawm cov kab mob tshwj xeeb ntawm tus nqi ntawm Parkinsonism nyob rau hauv txhua tus (7,8).
Txoj kev
Cov neeg tuaj koom los ntawm 3 qhov kev tshawb fawb txuas ntxiv hauv zej zog los ntawm cov neeg koom nrog ntau haiv neeg, Kev Ntseeg Kev Cai Lij Choj (ROS), Rush Memory and Aging Project (MAP), thiab Minority Aging Research Study (MARS) (7,8). Cov neeg koom nrog tau cuv npe yam tsis paub tias dementia thiab pom zoo rau kev soj ntsuam txhua xyoo thiab autopus. Cov neeg koom nrog ROS thiab MAP feem ntau yog cov neeg Caucasian Asmeskas thiab cov neeg koom nrog MARS yog txhua tus neeg Asmeskas Asmeskas. Qhov tseem ceeb, tag nrho 3 txoj kev tshawb fawb qhia ib qho tseem ceeb ntawm kev sim roj teeb thiab cov qauv kev soj ntsuam kuaj mob thiab lub hlwb autopsy ua kom muaj kev sib koom ua ke raws li peb tau ua hauv cov kev tshawb fawb yav dhau los (1). Cov ntaub ntawv leveraged hauv txoj kev tshawb fawb no yog los ntawm ntau qhov kev tshawb fawb tsis tu ncua. Feem ntau ntawm cov tib neeg (1024/1087, 94 feem pua) nyob rau hauv txoj kev tshawb no tau suav nrog hauv cov ntawv tshaj tawm ua ntej uas tsom tshwj xeeb rau kev paub txog kev poob qis (6). Nyob rau hauv qhov sib piv rau qhov kev kawm ua ntej no, txoj kev tshawb fawb tam sim no tau tshuaj xyuas cov ntaub ntawv ntxiv los txiav txim seb tus neeg mob tshwj xeeb ntawm lub paj hlwb pathologies mus rau kev loj hlob parkinsonism, ntxiv cov ntaub ntawv los ntawm cov neeg laus ntxiv, thiab suav nrog cov ntsuas ntawm Parkinson's disease (PD) pathology. Thaum lub sij hawm ntawm cov kev ntsuam xyuas no, 4084 cov neeg laus tau raug xaiv rau cov kev tshawb fawb no. Ntawm cov no, 1430 tuag thiab ua rau lub hlwb autopsy thiab muaj 2 lossis ntau qhov kev ntsuam xyuas siv tau ntawm parkinsonism ua ntej tuag rau kev txheeb xyuas ntawm tus nqi ntawm Parkinsonism. Parkinsonism yog ib pawg ntawm cov kab mob sib txawv uas cuam tshuam rau cov neeg laus. Txij li qhov kev loj hlob ntawm parkinsonism txawv ntawm cov neeg laus nrog thiab tsis muaj kev kuaj mob ntawm PD thiab lawv lub hauv paus pathologic txawv, raws li tau ua hauv kev tshawb fawb ua ntej ntawm parkinsonism, peb tsis suav nrog 52 tus neeg laus nrog kev kuaj mob ntawm PD (1). Ntawm 1378 tus neeg mob ntxiv, 1089 muaj cov ntaub ntawv tiav rau tag nrho 9 qhov ntsuas ntawm lub hlwb pathologies txheeb xyuas hauv txoj kev tshawb no (MAP, n=587; ROS, n=483, thiab MARS, n=19) . Lawv cov yam ntxwv kho mob thiab tom qab tuag tau sau tseg hauv Table 1.
Kev soj ntsuam ntawm Parkinsonism
Cov txiaj ntsig ntawm cistanche tubulosa-Anti Parkinson tus kab mob
Thaum kuaj txhua xyoo, cov kws kho mob tau soj ntsuam Parkinsonian gait, rigidity, bradykinesia, thiab tshee txhua xyoo siv 26 yam khoom los ntawm kev hloov kho United Parkinson's Disease Rating Scale (UPDRS). Cov kev ntsuas no muaj kev ntseeg siab ntawm kev sib raug zoo thiab kev ruaj ntseg nyob rau lub sij hawm luv luv ntawm cov kws saib xyuas neeg mob thiab muab piv nrog tus kws kho mob tshwj xeeb (9-11).
Table 1. Clinical and Pathology Measures of Analytic Cohort (N=1089)
Ntiaj teb Parkinsonian Score
Kev ntsuas tas mus li ntawm Parkinsonism yog qhov tseem ceeb rau kev tshuaj xyuas cov koom haum ntawm postmortem indices nrog kev nce qib ntawm Parkinsonism. Ib qho qhab nia rau txhua qhov ntawm 4 Parkinsonian cov cim qhia tau ua raws li cov lej ntawm cov qhab nia rau txhua yam ntawm nws cov khoom ntsuas nrog UPDRS. Cov qhab nia rau 4 Parkinsonian cov cim qhia tau nruab nrab los muab cov qhab nia Parkinsonian thoob ntiaj teb txuas ntxiv raws li tau piav qhia yav dhau los (1).
Clinical Parkinsonism qeb
Kev ntsuas categorical ntawm parkinsonism yog qhov tsim nyog los kwv yees cov xwm txheej ntawm qhov xwm txheej parkinsonism. Ib pawg Parkinsonism uas tau lees paub yav dhau los tau tsim ua raws li tus lej ntawm 4 Parkinsonian cov paib tam sim no nrog UPDRS kev ntsuas. Daim paib Parkinsonian tau tshwm sim yog tias 2 lossis ntau dua ntawm nws cov khoom tau qhab nia ua qhov txawv txav me me lossis hnyav dua. Clinical parkinsonism tshwm sim yog tias tsawg kawg 2 ntawm 4 cov paib parkinsonian tshwm sim (11).
Clinical Diagnosis of PD
Kev kuaj mob ntawm PD yog nyob ntawm cov ntaub ntawv kho mob thiab cov ntaub ntawv qhia tus kheej raws li tau tshaj tawm yav dhau los (1).
Suav tshuaj ntsuab cistanche-Anti Parkinson's disease
Demographic Covariates
Hnub yug thiab poj niam txiv neej tau sau los ntawm kev sib tham nrog cov neeg koom. Hnub nyoog hauv xyoo raug xam los ntawm tus kheej qhia hnub yug thiab hnub tuag. Kev soj ntsuam ntawm lub hlwb Pathology Kev tshem tawm lub hlwb, kev faib cov ntaub so ntswg, thiab kev khaws cia, thiab ib qho kev kuaj xyuas tag nrho thiab cov kab mob microscopic nrog rau qhov muaj pes tsawg leeg ntawm postmortem indices ua raws li tus qauv txheej txheem. Rau cov kev tshuaj ntsuam no, peb dichotomized txhua ntawm 9 pathologies uas tau ntsuas (12). Degenerative Pathologies Parkinson's disease Pathology Nigral neuronal poob tau raug soj ntsuam nyob rau hauv ntu los ntawm substantia nigra siv ib nrab-quantitative scale (0-3). Lewy lub cev kab mob pathology tau soj ntsuam nyob rau hauv xya lub paj hlwb siv cov tshuaj monoclonal phosphorylated antibody (Zymed; 1:50) rau -synuclein thiab tau kho raws li tam sim no lossis tsis nyob hauv cov kev tshuaj ntsuam no. PD pathology txhais tau tias yog nruab nrab mus rau hnyav nigral neuronal poob thiab muaj lub cev Lewy raws li tau tshaj tawm yav dhau los (1). Alzheimer's Pathology Alzheimer's kab mob pathology (piv txwv li, neuritic plaques, diffuse plaques, thiab neurofibrillary tangles) tau pom los ntawm kev hloov kho Bielschowsky nyiaj stain ntawm ntu los ntawm 5 lub paj hlwb thaj tsam thiab kev kuaj mob ntawm pathologic AD tau txiav txim siab raws li kev hloov kho cov lus pom zoo ntawm National Institute of Agence. (NIA)–Reagan cov txheej txheem (piv txwv li, nruab nrab lossis siab tshaj) (13). Transactive Response DNA-Binding Protein 43 Lub xub ntiag ntawm transactive teb DNA-binding protein 43 (TDP-43) cytoplasmic inclusions tau txiav txim siab siv cov tshuaj tiv thaiv rau phosphorylated TDP-43 (pS409/410; 1:100); TDP-43 kev faib tawm tau muab faib ua 3 theem (theem 1, thaj chaw rau amygdala; theem 2, txuas ntxiv mus rau hippocampus lossis entorhinal cortex; theem 3, txuas ntxiv mus rau neocortex) thiab TDP-43 tau txiav txim siab tam sim no yog tias zoo rau theem 2 lossis 3 (14).
Hippocampal Sclerosis
Lub xub ntiag ntawm hippocampal sclerosis tau soj ntsuam unilaterally nyob rau hauv ib tug coronal seem thiab muab qhab nia raws li tsis tuaj los yog tam sim no raws li loj neuronal poob thiab gliosis nyob rau hauv CA1 thiab / los yog subiculum (15).
Cerebrovascular Disease Pathology
Macroscopic Cerebral Infarcts
Peb tau tshuaj xyuas 1-cm slabs thiab pom cerebral infarcts los ntawm qhov muag liab qab tau lees paub tias microscopically, raws li tau tshaj tawm yav dhau los. Macroinfarcts raug kho raws li tam sim no lossis tsis tuaj rau cov kev tshuaj ntsuam no. Microinfarcts Cov kab mob microinfarcts tau txheeb xyuas cov kab mob microscopically siv H&E stains ntawm 9 lub paj hlwb raws li tau piav qhia dhau los. Microinfacts raug kho raws li tam sim no lossis tsis tuaj rau cov kev tshuaj ntsuam no. Atherosclerosis Cerebral nruab nrab- mob hnyav atherosclerosis raug soj ntsuam ntawm tag nrho cov kev ntsuam xyuas ntawm lub anterior, nruab nrab, thiab posterior cerebral hlab ntsha thiab lawv cov ceg ze ze ntawm lub voj voog ntawm Willis. Arteriolosclerosis Peb tau soj ntsuam cov hlab ntsha ntawm cov hlab ntsha ntawm lub hauv siab basal ganglia siv H&E stained seem los txiav txim siab nruab nrab-mob cerebral arteriolosclerosis (16). Cerebral Amyloid Angiopathy Immunohistochemistry tau siv los txheeb xyuas qhov nruab nrab-hnyav-amyloid deposition hauv meningeal thiab parenchymal hlab ntsha hauv 5 thaj chaw neocortical (17).
Kev Tshawb Fawb Txog Kev Tshawb Fawb
Cov zaus ntawm txhua lub hnub nyoog ntsig txog neuropathologies raug tshaj tawm. Raws li peb tau ua hauv kev tshaj tawm ua ntej, peb tau siv lub hauv paus hloov pauv rau qhov qhab nia Parkinsonism thoob ntiaj teb. Siv txhua xyoo cov qhab nia thoob ntiaj teb parkinsonism raws li qhov txiaj ntsig txuas ntxiv mus ntev, peb siv cov qauv sib xyaw ua ke los tshuaj xyuas cov koom haum ntawm cov ntsuas neuropathologic nrog kev nce qib parkinsonism ntau xyoo ua ntej tuag. Cov qauv no tswj rau hnub nyoog thiab poj niam txiv neej. Thawj tus qauv tau teev tseg raws li hauv qab no, qhia txog qhov pom Parkinsonism qhab nia rau cov neeg koom nrog kuv ntawm lub sijhawm j los ntawm yij thiab muaj cov neuropathologic index k rau cov neeg koom nrog I los ntawm Xik, qhov twg kuv=1 ... N, j=1 … mi, and k=1 … K. The score yij is estimated by 0 plus K k=1 Xik k plus 0tij plus K k =1 Xik ktij plus i0 plus i1tij. Lub sij hawm tij hais txog lub sij hawm nyob rau hauv xyoo ua ntej tuag. Kev hloov kho tus nqi ntawm kev nce qib parkinsonism tau kwv yees los ntawm 0 thiab kev koom tes ntawm kth neuropathology nrog kev nce qib parkinsonism tau kwv yees los ntawm k. Tshwj xeeb tshaj yog, tus qauv specification tau tso cai rau peb los tshuaj xyuas qhov cuam tshuam ntawm cov neuropathologies tshwj xeeb ntawm Parkinsonism thaum coj mus rau hauv tus account txhua tus neeg ua ke ntawm neuropathologies (piv txwv li, ntawm ib tus neeg tshwj xeeb). Tshwj xeeb, rau cov neeg koom nrog kuv, tag nrho cov kev loj hlob ntawm parkinsonism nyob rau tag nrho lub sij hawm kawm txuam nrog cov neeg koom nrog cov kev sib xyaw tshwj xeeb ntawm K neuropathologies tau kwv yees los ntawm K k=1 Xik ktimi; ces, qhov kev faib ua feem ntawm kev loj hlob parkinsonism vim ib tug pathology k raug xam raws li Xik k/ K k=1 Xik k. Kev faib tawm ntawm tib neeg cov kev faib ua feem ntawm kev nce qib ntawm parkinsonism suav los ntawm txhua tus neuropathology tau kuaj pom thiab cov ntaub ntawv sau tseg tau siv los txheeb xyuas qhov cuam tshuam ntawm txhua tus neuropathology ntawm parkinsonism. Kev txheeb xyuas txheeb cais tau ua tiav siv SAS / STAT software, version 9.4 rau Linux (SAS Institute Inc, Cary, NC). Cov qauv raug tswj rau hnub nyoog thiab poj niam txiv neej. Kev txheeb xyuas qhov tseem ceeb tau txiav txim siab ntawm qib .05.
Superman tshuaj ntsuab cistanche-Anti Parkinson tus kab mob
Cov txiaj ntsig
Clinical thiab Postmortem yam ntxwv ntawm Analytic Cohort
Muaj 1089 tus neeg laus suav nrog hauv cov kev tshuaj ntsuam no thiab lawv cov tsos mob tshwm sim ze rau qhov tuag tau sau tseg hauv Table 1. Lub sijhawm ntau tshaj 8.5 xyoo ntawm kev soj ntsuam (txhais tau tias 8.7, SD=4.82 xyoo) , ntau dua 50 feem pua tau pom cov pov thawj ntawm parkinsonism ntawm lawv qhov kev ntsuam xyuas zaum kawg uas yog nyob rau nruab nrab 1.6 xyoo ua ntej tuag. Peb dichotomized PD pathology thiab lwm yam 8 pathologies ntsuas los suav pes tsawg pathologies tau soj ntsuam hauv txhua tus neeg. Alzheimer's kab mob yog cov feem ntau pom pathology, nrog 65 feem pua ntawm tag nrho cov neeg tuaj koom qhia cov pov thawj ntawm pathologic AD raws li NIA Reagan cov qauv. Cerebrovascular pathologies thiab TDP-43 txhua tus cuam tshuam txog 1/3 ntawm cov neeg koom. Hippocampal sclerosis thiab PD tsis tshua muaj cuam tshuam rau 10 feem pua lossis tsawg dua ntawm cov neeg koom (Table 1). Sib nrug ntawm AD, qhov muaj cov kab mob degenerative tsis tshua muaj ntau dua li kab mob cerebrovascular (CVD) (Table 1). Ib lossis ntau qhov pathologies tau pom nyob rau hauv yuav luag txhua tus neeg (91.9 feem pua). Alzheimer tus kab mob ib leeg tshwm sim hauv tsuas yog 9 feem pua ntawm cov neeg mob. Kwv yees li 79 feem pua muaj 2 lossis ntau dua, 55 feem pua 3 lossis ntau dua, 28 feem pua muaj 4 lossis ntau dua, thiab 11 feem pua muaj 5 lossis ntau dua pathologies. Tus neeg nruab nrab muaj 3 kab mob (qhov nruab nrab 3; Q1–Q3, 2.0).
Association of Brain Pathologies Nrog Progressive Parkinsonism
Peb tau tshuaj xyuas qhov kev nce qib ntawm Parkinsonism siv cov qauv sib xyaw ua ke uas suav nrog cov ntsiab lus rau lub sijhawm, hnub nyoog, thiab poj niam txiv neej thiab lawv cov kev cuam tshuam nrog lub sijhawm. Qhov nruab nrab parkinsonism nce los ntawm 0.13/xyoo (kwv yees=0.127, SE 0.005, p < .001), uas yog sib npaug rau ib tus neeg lub ntsiab lus parkinsonism poob los ntawm kwv yees li 9 feem pua ntawm SD / xyoo. Tus nqi ntawm kev vam meej parkinsonism tsis txawv ntawm poj niam txiv neej lossis haiv neeg (cov txiaj ntsig tsis pom). Peb mam li ntxiv cov ntsiab lus rau 9 lub hlwb pathologies thiab lawv cov kev cuam tshuam nrog lub sijhawm. Parkinson tus kab mob, microinfarcts, atherosclerosis, arteriolosclerosis, thiab cerebral amyloid angiopathy yog nws tus kheej cuam tshuam nrog tus nqi ntawm Parkinsonism, tab sis tsis yog AD, TDP-43, hippocampal sclerosis, thiab microinfarcts (Table 2, Parkinsonism 1). Lub koom haum ntawm pathologies nrog tus nqi ntawm kev loj hlob parkinsonism tsis txawv ntawm poj niam txiv neej lossis haiv neeg (cov txiaj ntsig tsis pom). Peb rov ua cov qauv sib xyaw ua ke nrog rau cov ntsiab lus rau 5 pathologies uas tau ua rau nws tus kheej cuam tshuam nrog kev nce qib parkinsonism (Table 2, Parkinsonism 2). Peb kwv yees qhov kev txhim kho nyob rau hauv tus qauv haum, uas yog, qhov feem pua ntawm qhov sib txawv ntawm kev nce qib ntawm parkinsonism suav nrog tom qab ntxiv cov ntsiab lus rau pej xeem covariates thiab indices rau 5 pathologies txheeb ze rau tus qauv siv yam tsis muaj covariates. Tus qauv tag nrho tau pom tias muaj kev txhim kho tseem ceeb hauv cov qauv haum xws li qhov sib txawv ntawm cov nyiaj tau los ntawm 21 feem pua. Tshwj xeeb, qhov ntsuas ntawm lub hlwb pathology suav txog 13 feem pua, PD pathology suav txog 2 feem pua, thiab CVD pathologies 11 feem pua.
Cov tib neeg-Specific contribution of pathologies to Progressive Parkinsonism
Cov kev pab tshwj xeeb ntawm txhua tus pathology yog raws li lub zog ntawm nws cov koom haum nrog kev loj hlob parkinsonism (Table 2, Parkinsonism 2) nrog rau kev sib txawv ntawm cov pathologies ntsuas hauv txhua tus neeg. Raws li lub hlwb pathologies nquag sib koom ua ke, peb pom 31 qhov sib xyaw ua ke ntawm pathologies ntawm nws tus kheej cuam tshuam nrog kev nce qib ntawm Parkinsonism hauv pawg no (Daim duab 1). Ib lossis ntau dua ntawm CVD pathologies yog cov kab mob feem ntau cuam tshuam nrog kev ua haujlwm ntawm Parkinsonism (n=830, 76.2 feem pua). Parkinson tus kab mob pathology tsis tshua muaj tshwm sim (n=88, 8.1 feem pua). Parkinson tus kab mob pathology yog cov kab mob tshwj xeeb hauv 14 tus neeg (1.3 feem pua), tab sis feem ntau tshwm sim ua ke nrog ib lossis ntau dua CVD pathologies (n=74, 6.8 feem pua). Rau txhua tus neeg, peb tau txiav txim siab qhov kev faib ua feem ntawm kev loj hlob parkinsonism uas tau suav los ntawm txhua tus ntawm 5 pathologies cuam tshuam nrog kev nce qib parkinsonism. Cov ntaub ntawv no tau muab sau tseg rau hauv Table 3 thiab piav qhia rau txhua tus kab mob hauv daim duab 2. Thaum PD pathology tsis tshua muaj tshwm sim, thaum tam sim no suav txog ntau dua 60 feem pua ntawm cov neeg mob Parkinsonism. Cerebral amyloid angiopathy uas yog 4 zaug ntau dua li PD muaj qhov cuam tshuam zoo sib xws rau kev nce qib parkinsonism. Txawm li cas los xij, raws li tuaj yeem pom los ntawm ntau yam rau txhua yam ntawm cov kab mob no (Table 3; Daim duab 2), qhov txiaj ntsig tiag tiag ntawm txhua tus kab mob sib txawv vim muaj ntau qhov sib xyaw ntawm cov kab mob sib xyaw (Daim duab 1).
Cistanche experience-Anti Parkinson's disease
Kev sib tham
Txoj kev tshawb fawb tam sim no tau sim qhov kev xav tias tus neeg tshwj xeeb cuam tshuam ntawm tib neeg lub hlwb pathologies cuam tshuam nrog kev loj hlob parkinsonism txawv ntawm cov neeg laus (6). Tus neeg tshwj xeeb cuam tshuam ntawm lub paj hlwb sib txawv nyob ntawm lub zog ntawm nws txoj kev koom tes nrog kev loj hlob ntawm Parkinsonism thiab nws cov kev cuam tshuam sib luag hauv ib tus neeg uas yuav sib txawv nrog cov naj npawb ntawm cov kab mob comorbid tam sim no. Ua ntej, peb txiav txim siab lub zog ntawm cov koom haum ntawm lub hlwb pathologies ntawm nws tus kheej cuam tshuam nrog kev vam meej parkinsonism. Parkinson tus kab mob pathology thiab ob peb qhov ntsuas ntawm CVD pathologies tau ntawm nws tus kheej cuam tshuam nrog kev ua haujlwm ntawm Parkinsonism thiab suav txog 13 feem pua ntawm nws qhov sib txawv. Lwm qhov ntsuas ntawm lub hlwb pathology suav nrog AD, TDP-43, hippocampal sclerosis, thiab microinfacts tsis cuam tshuam nrog kev nce qib parkinsonism. Lub paj hlwb pathologies nquag sib koom ua ke, thiab peb tau pom 31 qhov sib xyaw ua ke ntawm 5 pathologies ntawm nws tus kheej cuam tshuam nrog kev nce qib parkinsonism. Yog li ntawd, tus neeg tshwj xeeb cuam tshuam ntawm txhua tus ntawm 5 pathologies sib txawv ntawm cov neeg laus sib txawv vim tias muaj coob tus neeg sib xyaw ua ke ntawm kev sib xyaw ua ke uas tshwm sim. Cov kev tshawb pom no qhia tias muaj ntau dua heterogeneity nyob rau hauv comorbidity thiab txheeb ze cuam tshuam ntawm ib tug neeg lub hlwb pathologies txuam nrog kev loj hlob parkinsonism dua yav tas los paub thiab qhov no tej zaum yuav suav ib feem rau nws phenotypic heterogeneity nyob rau hauv cov neeg laus. Cov kab mob cerebrovascular pathologies ib leeg lossis hauv kev sib xyaw ua ke yog cov kab mob uas muaj feem cuam tshuam nrog kev nce qib Parkinsonism tau pom nyob hauv ntau dua 75 feem pua ntawm cov tib neeg. Ntawm qhov tod tes, PD pathology tsis tshua muaj tshwm sim (8 feem pua) thiab feem ntau pom ua ke nrog CVD pathologies (6.7 feem pua). Yog li, feem ntau ntawm cov neeg uas muaj CVD pathologies tsis muaj pov thawj ntawm PD pathology. Thaum PD pathology tsis tshua muaj tshwm sim, hauv cov tib neeg uas nws tau tshwm sim nws qhov kev cuam tshuam suav txog ntau dua 60 feem pua ntawm cov neeg mob Parkinsonism. Txawm li cas los xij, raws li tau piav qhia hauv daim duab 2, qhov kev faib ua feem ntawm PD pathology cuam tshuam rau tus neeg koom nrog sib txawv. Qhov kev hloov pauv no ntawm qhov cuam tshuam ntawm PD thiab lwm yam CVD pathologies tau muab los ntawm ntau qhov sib xyaw ua ke ntawm cov kab mob comorbid uas cuam tshuam nrog kev loj hlob parkinsonism pom nyob rau hauv daim duab 1. Cov txiaj ntsig no qhia qhov txawv txav ntawm tus neeg tshwj xeeb cuam tshuam ntawm ib tus neeg pathologies cuam tshuam nrog kev loj hlob parkinsonism. Cov neeg laus tuaj yeem suav nrog ib feem ntawm kev kho mob heterogeneity ntawm parkinsonism. Cov ntaub ntawv no qhia tias muaj ntau dua heterogeneity nyob rau hauv lub hlwb comorbid pathologies uas muaj nyob rau hauv cov laus lub hlwb thiab lawv ua rau muaj kev cuam tshuam rau kev loj hlob parkinsonism tshaj li hais los ntawm cov kev tshawb fawb ua ntej (1). Ntxiv mus, cov ntaub ntawv no qhia tias CVD pathologies yuav muaj kev cuam tshuam loj dua rau kev loj hlob ntawm Parkinsonism hauv cov neeg laus uas tsis muaj kev kuaj mob ntawm PD dua li PD pathology. Cov ntaub ntawv postmortem no yuav muaj qhov cuam tshuam tseem ceeb rau kev tshawb fawb txog kev laus vim nws qhia tias Parkinsonism thiab cov neeg laus yog ib qho kev tsis sib haum xeeb thiab qhia tias parkinsonism hauv cov neeg laus yog qhov ua ntej rau kev sib sau ntawm PD pathology tsis tshua muaj. Tsis tas li ntawd, vim tsis muaj kev kho mob tam sim no rau PD pathology thiab vim tias Parkinsonism feem ntau cuam tshuam nrog kev sib sau ntawm CVD pathologies, parkinsonism hauv cov neeg laus tuaj yeem ua rau muaj kev kub ntxhov ntawm kev pheej hmoo vascular thiab kab mob. Qhov no qhia txog qhov xav tau rau CVD cov qhab nia txaus ntshai uas tuaj yeem ua rau cov tib neeg muaj kev pheej hmoo rau cov kab mob CVD tshwj xeeb, uas yog, microinfarcts piv rau microvascular pathologies, thiab cov kev xav tau sib txuas rau cov phiaj xwm kev kho mob nrog rau qhov tshwj xeeb ntxiv rau ntau yam CVD pathologies uas suav nrog hauv cov hlwb laus. Kev soj ntsuam ze dua ntawm peb cov txiaj ntsig tau ua rau pom lwm qhov tseem ceeb ntawm kev tshawb nrhiav txog qhov sib txawv ntawm lub neej lig lub cev muaj zog cuam tshuam los ntawm qhov ntsuas ntawm lub hlwb pathologies. Raws li qhia rau lwm cov phenotypes lub cev muaj zog, qhov ntsuas ntawm lub paj hlwb pathologies hauv txoj kev tshawb no suav rau cov neeg tsawg (<15%) of the variance of progressive parkinsonism as compared to reports that these same indices account for up to 50% of the variance of cognitive decline (18– 20). Several potential reasons may account for the disparity in the variance accounted for by brain pathologies between motor and cognitive phenotypes. First, the instruments used to assess motor function may not capture motor phenotypes with the same fidelity as cognitive testing. Moreover, the indices of brain pathologies used in these analyses were collected in mostly cognitive brain regions and may not fully capture the pathologic basis of progressive parkinsonism. While the movement is a volitional behavior that depends on healthy brain function, its control derives from pathways that extend outside the brain, traversing the entire CNS to reach the peripheral muscle, the final effector of all movement. In contrast, the majority of cognitive networks which subserve cognition reside within the brain. Thus, estimates of the variance of parkinsonism accounted for by brain indices alone may underestimate the full extent to which these age-related pathologies affect parkinsonism without measuring the pathology's presence throughout the entire extent of central and peripheral motor pathways (21,22). The current results highlight the complexity of accumulating mixed-brain pathologies in aging brains and inform on their contribution to the phenotypic heterogeneity of progressive parkinsonism. This emphasizes the need for new analytic tools which can incorporate the many combinations of mixed-pathologies that accumulate in aging brains into analyses that seek to elucidate the pathologic substrate of important aging phenotypes. These findings also emphasize the difficulties faced by investigators in trying to develop treatments for mixed pathologies or run clinical trials for a single brain pathology without accounting for the many combinations of comorbid pathologies in older adults (7). This common occurrence of mixed-brain pathologies may account in part for the dismal success of developing drug treatments focusing on a specific pathology like AD or PD. Further work focusing on the molecular drivers of these pathologies may identify unique genes or proteins which drive distinct pathologies that can be targeted in further drug discovery for the development of novel therapies (23–25). In the interim, there may be increased utility in focusing aging research efforts on identifying behaviors like physical activity or other lifestyles which may provide reserve or resilience for older adults which may mitigate the untoward effects of mixed-brain pathologies even in the absence of efficacious treatments targeting specific pathologies (26). The study has strengths and weaknesses. Findings are based on large numbers of older adults who underwent structured assessments of Parkinsonism with a validated instrument (9). Autopsy rates were very high, 9 age-related brain pathologies were measured, and the statistical approach leveraged person-specific information. The study also has several limitations. These findings are from a selected cohort which will need to be replicated in population-based studies. These analyses were based on dichotomized pathology variables. This was done to facilitate a comparison between Parkinsonism and different pathologies. Despite this limitation, the large number of combinations of pathologies related to different phenotypes suggests that calculating a pathology burden score may help visualize and analyze the role of mixed-brain pathologies in older adults (1). Not all known pathologies were measured, that is, brain white matter integrity, and there is increasing evidence that molecular mechanisms which drive late-life motor impairment may not manifest exclusively through known pathologies (18,24).
Rooj 2. Cov koom haum ntawm lub hlwb patchologies nrog tus nqi txhua xyoo ntawm kev vam khom cov chaw nres tsheb thiab kev txawj xav
Daim duab 1. Kev sib xyaw ua ke ntawm cov kab mob hauv lub hlwb ntawm nws tus kheej cuam tshuam nrog kev loj hlob ntawm Parkinsonism. Daim duab no qhia txog lub nra ntawm cov kab mob sib xyaw ua ke ntawm nws tus kheej cuam tshuam nrog kev loj hlob parkinsonism hauv lub hlwb laus. Daim ntawv qhia bar nyob rau sab laug ces kaum qhia cov zaus ntawm ib tus neeg lub hlwb pathologies indices sau nyob rau hauv txoj kev tshawb no. Txuas cov dots dub ntawm x-axis qhia txog kev sib xyaw ua ke ntawm lub hlwb pathology hauv 5 lossis ntau tus neeg. Histograms nyob rau hauv lub ntsiab vaj huam sib luag qhia cov zaus ntawm lub hlwb pathology indices rau cov neeg uas muaj thiab tsis muaj parkinsonism ze rau kev tuag (parkinsonism tam sim no [xiav] piv rau parkinsonism tsis tuaj [dub]), txiav txim los ntawm lawv zaus. Qhov siab ntawm txhua lub bar sib raug rau tus naj npawb ntawm cov neeg nrog txhua qhov sib xyaw ua ke. PD=PD pathology; CAA=cerebral amyloid angiopathy. Raws li tau piav qhia hauv daim duab, lub paj hlwb pathology feem ntau tshwm sim. Cov kab mob cerebrovascular pathologies ib leeg lossis hauv kev sib xyaw ua ke yog cov kab mob feem ntau cuam tshuam txog kev mob Parkinsonism. Nws tsis tshua muaj tshwm sim rau PD pathology tshwm sim ib leeg, thiab nws feem ntau pom ua ke nrog ib lossis ntau tus kab mob cerebrovascular pathologies.
Table 3. Kev Pabcuam Tib Neeg-Specific ntawm Tib Neeg Lub Plawv Pathologies rau tus nqi ntawm Progressive Parkinsonism thiab kev paub tsis meej
Daim duab 2. Tus neeg tshwj xeeb feem ntawm kev loj hlob parkinsonism cuam tshuam nrog cov kab mob hauv lub hlwb. Histogram uas qhia qhov zaus (x-axis) thiab tib neeg cov kev faib ua feem ntawm kev nce qib parkinsonism (x-axis) suav nrog txhua tus ntawm 5 kab mob ntsig txog kev mob parkinsonism. PD=PD pathology; CAA=cerebral amyloid angiopathy.
Cov ntaub ntawv
1. Buchman AS, Yu L, Wilson RS, et al. Progressive parkinsonism nyob rau hauv cov neeg laus muaj feem xyuam rau lub nra ntawm lub hlwb sib xyaw pathologies. Neurology. Xyoo 2019; 92: e1821–e1830. doi 10.1212/wnl.0000000000007315
2. Boyle PA, Yang J, Yu L, et al. Ntau yam teebmeem ntawm hnub nyoog ntsig txog neuropathologies ntawm txoj hauv kev ntawm kev paub txog lub neej lig poob. Lub hlwb. 2017; 140: 804–812. doi: 10.1093/brain/aww341
3. Wilson RS, Capuano AW, Bennett DA, Schneider JA, Boyle PA. Cov chav kawm ib ntus ntawm cov teebmeem neurodegenerative ntawm kev paub hauv lub hnub nyoog laus. Neuropsychology. 2016; 30:591–599. doi: 10.1037/neu0000282
4. Yu L, Boyle PA, Nag S, et al. APOE thiab cerebral amyloid angiopathy hauv cov neeg laus hauv zej zog. Neurobiol Kev laus. 2015; 36:2946–2953. doi: 10.1016/j.neurobiolaging.2015.08.008.
5. Boyle PA, Wilson RS, Yu L, et al. Feem ntau ntawm kev paub txog lub neej poob qis tsis yog vim muaj cov kab mob neurodegenerative. Ann Neurol. 2013; 74:478–489. doi: 10.1002/ana.23964 ib
6. Boyle PA, Yu L, Wilson RS, Leurgans SE, Schneider JA, Bennett DA. Tib neeg kev koom tes ntawm neuropathologies rau kev paub tsis meej thaum muaj hnub nyoog laus. Ann Neurol. 2018; 83:74–83. doi: 10.1002/ana.25123
7. Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, Schneider JA. Kev cai dab qhuas Orders Study and Rush Memory and Aging Project. J Alzheimers Dis. 2018; 64:S161–S189. doi: 10.3233/jad-179939
8. Barnes LL, Shah RC, Aggarwal NT, Bennett DA, Schneider JA. Txoj Kev Tshawb Fawb Txog Kev Laus Me Me: Kev siv zog txuas ntxiv kom tau txais lub hlwb pub dawb hauv African Asmeskas yam tsis muaj dementia. Curr Alzheimer Res. 2012; 9:734–745. doi: 10.2174/156720512801322627
9. Bennett DA, Shannon KM, Beckett LA, Wilson RS. Dimensionality ntawm parkinsonian cov cim qhia hauv kev laus thiab Alzheimer's kab mob. J Gerontol A Biol Sci Med Sci. 1999; 54:M191–M196. doi: 10.1093/gerona/54.4.m191
10. Bennett DA, Shannon KM, Beckett LA, Goetz CG, Wilson RS. Metric zog ntawm cov kws saib xyuas neeg mob cov kev ntsuam xyuas ntawm Parkinsonian cov paib nrog hloov kho Unified Parkinson's Disease Rating Scale. Neurology. 1997; 49:1580–1587. doi 10.1212/wm.49.6.1580
11. Buchman AS, Wilson RS, Shulman JM, Leurgans SE, Schneider JA, Bennett DA. Parkinsonism nyob rau hauv cov neeg laus thiab nws cov koom haum nrog kev noj qab haus huv tshwm sim thiab neuropathology. J Gerontol A Biol Sci Med Sci. 2016; 71:549–556. doi: 10.1093/gerona/glv153
12. Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS. Txheej txheem cej luam thiab kev tshawb pom los ntawm Rush Memory thiab Aging Project. Curr Alzheimer Res. 2012; 9:646–663. PIB: 10.2174/156720512801322663
13. Bennett DA, Wilson RS, Boyle PA, Buchman AS, Schneider JA. Kev sib raug zoo ntawm neuropathology rau kev paub hauv cov neeg uas tsis muaj kev paub tsis meej. Ann Neurol. 2012; 72:599–609. doi: 10.1002/ana.23654
14. Nag S, Yu L, Wilson RS, Chen EY, Bennett DA, Schneider JA. TDP-43 pathology thiab kev nco tsis zoo hauv cov neeg laus yam tsis muaj kev kuaj mob ntawm AD lossis FTLD. Neurology. 2017; 88:653–660. doi: 10.1212/ wm.0000000000003610
15. Nag S, Yu L, Capuano AW, et al. Hippocampal sclerosis thiab TDP-43 pathology hauv kev laus thiab Alzheimer's kab mob. Ann Neurol. 2015; 77:942–952. doi: 10.1002/ana.24388 ib
16. Buchman AS, Leurgans SE, Nag S, Bennett DA, Schneider JA. Kab mob cerebrovascular pathology thiab Parkinsonian cov cim qhia hauv cov laus. Mob stroke. 2011; 42:3183–3189. doi: 10.1161/strokeaha.111.623462
17. Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS, Bennett DA, Schneider JA. Cerebral amyloid angiopathy pathology thiab kev txawj ntse ntawm cov neeg laus. Ann Neurol. 2011; 69:320–327. doi: 10.1002/ana.22112
18. Buchman AS, Dawe RJ, Yu L, et al. Lub paj hlwb pathology muaj feem xyuam nrog tag nrho cov kev ua ub ua no txhua hnub hauv cov neeg laus. Neurology. 2018; 90:e1911–e1919. doi: 10.1212/NWS.0000000000005552
19. Buchman AS, Yu L, Wilson RS, et al. Post-mortem hlwb pathology muaj feem xyuam rau kev ua pa tsis ua haujlwm hauv cov neeg laus hauv zej zog. Pem Hauv Ntej Laus Neurosci. Xyoo 2015; 7:197. doi 10.3389/ua. Xyoo 2015.00197
20. Buchman AS, Yu L, Wilson RS, Boyle PA, Schneider JA, Bennett DA. Lub paj hlwb pathology pab txhawb rau kev hloov pauv ntawm lub cev tsis muaj zog thiab kev paub txog thaum muaj hnub nyoog laus. J Gerontol A Biol Sci Med Sci. 2014; 69:1536–1544. doi: 10.1093/gerona/glu117
21. Buchman AS, Leurgans SE, Nag S, et al. Spinal arteriolosclerosis yog tshwm sim nyob rau hauv cov neeg laus thiab txuam nrog parkinsonism. Mob stroke. 2017; 48: 2792–2798. doi: 10.1161/strokeaha.117.017643
22. Buchman AS, Nag S, Leurgans SE, et al. Spinal Lewy lub cev pathology hauv cov neeg laus uas tsis muaj kev kuaj mob antemortem ntawm Parkinson tus kab mob. Lub hlwb Pathol. 2018; 28:560–568. doi: 10.1111/bpa.12560
23. Buchman AS, Yu L, Petyuk VA, et al. Kev paub yuav txuas cortical IGFBP5 qib nrog lub cev muaj zog hauv cov neeg laus. PLoS Ib. Xyoo 2019; 14:e0220968. doi: 10.1371/journal.pone.0220968 ib
24. Yu L, Petyuk VA, Gaiteri C, et al. Targeted hlwb proteomics nthuav tawm ntau txoj hauv kev rau Alzheimer's dementia. Ann Neurol. 2018; 84:78–88. doi: 10.1002/ana.25266
25. Mostafavi S, Gaiteri C, Sullivan SE, et al. Lub network molecular ntawm cov laus tib neeg lub hlwb muab kev nkag siab rau hauv pathology thiab kev paub txog kev poob qis ntawm Alzheimer's disease. Neeb Neurosci. 2018; 21:811–819. doi: 10.1038/s41593-018-0154-9
26. Buchman AS, Yu L, Wilson RS, et al. Kev ua cev nqaij daim tawv, cov kab mob hauv lub hlwb, thiab kev paub txog hauv zej zog cov neeg laus laus. Neurology. Xyoo 2019; 92: e811–e822. doi 10.1212/wnl.0000000000006954 ib.
