Neuropathological Thiab Biomarker Nrhiav nyob rau hauv Parkinson's Disease Thiab Alzheimer's Disease: Los ntawm Protein Aggregates rau Synaptic Dysfunction
Aug 29, 2023
Abstract.
Muaj cov pov thawj ntxiv tias Parkinson's disease (PD) thiab Alzheimer's disease (AD) qhia txog cov cim qhia txog kev mob hlwb, thaum cov hom biomarkers zoo sib xws tau siv rau ob qho tib si. Hauv qhov kev tshuaj xyuas no peb tsom los tshawb txog qhov zoo sib xws thiab qhov sib txawv ntawm PD thiab AD ntawm ob qho tib si neuropathology thiab qib biomarker, tshwj xeeb yog tsom rau cov protein aggregates thiab synapse dysfunction. Yog li, amyloid-peptide (A) thiab tau qhov txhab ntawm Alzheimer's hom muaj nyob rau hauv PD, thiab -synuclein Lewy-type aggregates yog nquag tshawb pom hauv AD. Niaj hnub nimno neuropathological cov tswv yim ntxiv rau niaj hnub immunohistochemistry yuav ntxiv peb cov kev paub txog cov kab mob no tshaj cov protein aggregates thiab nqes mus rau lawv cov presynaptic thiab postsynaptic terminals, muaj peev xwm kho tau thiab txawm yav tom ntej kev cuam tshuam.
Nyob rau hauv xyoo tas los no, cov kws tshawb fawb tau tshawb pom muaj kev sib raug zoo ntawm synaptic dysfunction thiab kev tiv thaiv kab mob. Synaptic dysfunction yog ib qho mob uas tshwm sim hauv lub paj hlwb, uas cuam tshuam rau kev xav, nco, kev xav thiab lwm yam ntawm tib neeg lub cev, thiab cuam tshuam rau tib neeg lub neej txhua hnub thiab kev ua haujlwm. Kev tiv thaiv kab mob yog hais txog lub cev tiv thaiv lub peev xwm tiv thaiv kev cuam tshuam ntawm ntau yam kab mob, uas tuaj yeem tiv thaiv peb txoj kev noj qab haus huv.
Cov kev tshawb fawb pom tau hais tias kev sib raug zoo ntawm kev ua haujlwm ntawm synaptic thiab kev tiv thaiv kab mob yog kev cuam tshuam thiab cuam tshuam nrog ib leeg. Ntawm qhov tod tes, lub cev tiv thaiv kab mob tuaj yeem tswj hwm kev ua haujlwm ntawm synaptic thiab txo qhov tshwm sim ntawm kev ua haujlwm tsis zoo ntawm synaptic. Ntawm qhov tod tes, synaptic dysfunction tuaj yeem cuam tshuam rau kev tiv thaiv kab mob thiab ua rau muaj kev pheej hmoo kis mob rau tib neeg.
Lub cev tiv thaiv kab mob txo qhov tshwm sim ntawm synaptic dysfunction los ntawm cov txheej txheem tswj hwm. Hauv lub cev tiv thaiv kab mob, muaj cov kab mob tiv thaiv kab mob hu ua macrophages, uas tuaj yeem tshem tawm cov khib nyiab thiab cov khoom tsis zoo hauv synapses thiab tswj cov kev ua haujlwm ntawm synapses. Tsis tas li ntawd, qee cov molecules hauv lub cev tiv thaiv kab mob tuaj yeem khi rau cov molecules hauv cov neurons los tswj cov haujlwm ntawm cov neurons thiab tiv thaiv kev noj qab haus huv ntawm cov neurons.
Nyob rau hauv lem, synaptic dysfunction kuj muaj feem xyuam rau cov xwm txheej ntawm kev tiv thaiv. Ntau qhov kev tshawb fawb tau pom tias cov neeg uas muaj cov kab mob synaptic tsis zoo muaj lub cev tiv thaiv kab mob ua haujlwm tsis zoo thiab muaj feem cuam tshuam los ntawm cov kab mob thiab kab mob. Tsis tas li ntawd, synaptic dysfunction yuav ua rau kev xav thiab kev puas siab puas ntsws nyob rau hauv cov neeg mob, uas yuav cuam tshuam rau kev ua haujlwm ntawm lub cev thiab kev tiv thaiv kab mob.
Yog li ntawd, peb yuav tsum tau xyuam xim rau kev sib raug zoo ntawm synaptic dysfunction thiab kev tiv thaiv kab mob, tshwj xeeb tshaj yog thaum peb nyob rau hauv lub xeev ntawm kev ntxhov siab thiab ntxhov siab, peb yuav tsum tau xyuam xim tshwj xeeb rau peb lub cev noj qab haus huv, tswj tus cwj pwm zoo, nquag daws teeb meem, tswj. lub cev thiab lub hlwb sib npaug, thiab muaj kev noj qab haus huv zoo. Kev noj zaub mov zoo thiab kev noj qab haus huv txhawb nqa lawv txoj kev noj qab haus huv, kom lawv thiab lawv tsev neeg muaj kev noj qab haus huv, muaj zog tiv thaiv kab mob, thiab tiv thaiv kab mob. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco. Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche yog cov khoom siv tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm cov nqaij minced yog los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog carboxylic acid, polysaccharides, flavonoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.
Nyem Paub txhawm rau txhim kho lub cim xeeb luv luv
Kev txhais lus ntawm neuropathological discoveries rau lub tsev kho mob tseem nyuaj. Cerebrospinal kua (CSF) thiab positron emission tomography (PET) cov cim ntawm A thiab tau muaj kev ntseeg siab rau kev kuaj mob AD. Hloov pauv, CSF cov cim ntawm -synuclein tsis tau zoo ib yam. Hais txog PET cov cim, tsis muaj PET sojntsuam muaj rau -synuclein tsis tau, thaum AD PET cov cim muaj ntau yam los ntawm cov pov thawj zoo sib xws ntawm lawv qhov tshwj xeeb (amyloid imaging) mus rau qhov tsis paub tseeb ntawm lawv qhov kev ntseeg siab vim yog kev sib txuas ntawm lub hom phiaj (tau imaging). CSF synaptic markers yog qhov txaus nyiam tab sis tseem xav tau cov pov thawj ntxiv, uas tam sim no qhia tias cov no yuav yog cov cim tsis tshwj xeeb ntawm kev kis kab mob. Nws tuaj yeem txiav txim siab tias muaj cov pov thawj neuropathological uas cov protein sib sau ua ke ntawm AD thiab PD muaj nyob hauv ob qho tib si ntawm soma thiab synapse. Yog li, ob peb CSF thiab PET biomarkers dhau -synuclein, tau, thiab A tuaj yeem ntes cov ntsej muag sib txawv ntawm cov protein ntsig txog neurodegeneration. Nws tseem yuav pom tias qhov txiaj ntsig ntev npaum li cas thiab qhov muaj peev xwm muaj txiaj ntsig raws li cov cim surrogate ntawm cov biomarkers no.
Ntsiab lus:
-Synuclein, Alzheimer's disease, amyloid-, biomarkers, cerebrospinal kua, Lewy-type pathology, molecular imaging, Parkinson tus kab mob, synaptic dysfunction, tau.
Taw qhia
Ib feem tau los ntawm qhov tseeb tias dementia muaj ntau heev hauv Parkinson's disease (PD) [1], muaj cov pov thawj neuropathological uas PD thiab Alzheimer's disease (AD) muaj ntau yam sib txawv [2, 3]. Cov kev tshawb fawb tom qab-mortem neuropathological niaj hnub tam sim no tau ntxiv los ntawm biomarker kev tshawb fawb qhia txog qhov tshwm sim ntawm cov kab mob hauv vivo, xws li kev tshawb fawb biochemical hauv cerebrospinal kua (CSF) mus rau molecular imaging ntawm protein deposition xws li amyloid- (A) los yog tau. Ob hom kev tshawb fawb tau pom zoo nyob rau xyoo tas los no qhov kev xav tias cov kab mob neurofibrillary tangletype muaj xws li hyperphosphorylated tau thiab, tshwj xeeb tshaj yog, A-muaj aggregates muaj ntau hauv PD thiab cuam tshuam nrog qhov muaj thiab pheej hmoo ntawm, nrog rau lub sijhawm, dementia [2, 3. ]. Tag nrho cov no tau xav txog kev hloov pauv ntawm hom, tawm ntawm qhov kev xav dav dav ntawm qhov kawg ntawm 20th thiab thaum ntxov xyoo pua 21st tias cortical Lewy pathology ib leeg suav rau dementia hauv PD, kom pom tau tias Lewy thiab Alzheimer pathologies muaj feem cuam tshuam hauv PD-dementia. . Tsis tas li ntawd, tseem muaj cov ntaub ntawv zoo ib yam raws li kev sib koom ua ke ntawm -synuclein-muaj Lewy-type aggregates nyob rau hauv ib qho tseem ceeb ntawm ob qho tib si sporadic thiab tsev neeg AD, tshwj xeeb tshaj yog nyob rau hauv amygdala [4, 5].
Txawm li cas los xij, nws tseem tsis tau paub tias lub luag haujlwm tseem ceeb ntawm Lewy thiab Alzheimer pathologies tau pom nyob rau hauv cov kev tshawb fawb tom qab kev tuag, nrog rau kev thuam ntau tshaj yog tias cov no feem ntau cuam tshuam txog kev tshawb pom nyob rau theem kawg (tshwj tsis yog qhov kev txiav txim siab tau ua rau cov neeg mob tuag ntxov. ntawm tus kab mob tsis sib xws) thiab cov no yuav tsis tas yuav cuam tshuam dab tsi thaum xub thawj ua rau cov tsos mob (qhov no tseem ceeb dua, tab sis tsis tas li, dementia).
Raws li nyob rau hauv vivo biomarker cov kev tshawb fawb-los ntawm cov pov thawj ntawm kev sib koom ua ke ntawm ob leeg Lewy thiab Alzheimer pathologies nws tseem tsis tau muaj teeb meem vim nws tseem tsis tau paub meej tias cov biomarkers siv los cuam tshuam txog cov kab mob hauv qab los yog qhov tshwm sim ntawm qee cov txheej txheem molecular. Yog li, hauv cov kev tshawb fawb soj ntsuam CSF biomarkers, qhov kev txhawj xeeb tseem ceeb yog tias cov no yuav cuam tshuam txog cov kev hloov pauv tsis tshwj xeeb (feem ntau axonal poob lossis neuronal degeneration, nyob rau hauv cov ntaub ntawv ntawm tau [6]) los yog cov txheej txheem intrinsic muaj feem xyuam rau cov hom soluble ntawm cov protein koom nrog. (xws li synaptic dysfunction nyob rau hauv rooj plaub ntawm A [7] thiab -synuclein [8]), es tsis yog cov kab mob protein aggregates.
Ntawm no peb rov mus saib cov pov thawj neuropathological thiab biomarker los ntawm xyoo tas los no tsom rau cov kab mob pathology thiab synaptic dysfunction ntsig txog PD thiab AD cov kab mob ntsig txog cov proteins (-synuclein, A, thiab tau), muab cov no tso rau hauv kev xav thiab qhia cov lus qhia yav tom ntej.
NEUROPATHOLOGICAL EVIDENCE OF ASSOCIATION OF ALZHEIMER'S DISEASE-HOM PATHOLOGY nrog LEWY PATHOLOGY IN PARKINSON'S DISEASE
Nyob rau hauv pre-synuclein era thaum kev ntsuam xyuas ntawm cortical Lewy lub cev yog ua tau, tab sis ntau nyuaj thiab tsawg txhim khu kev qha, ib co kev tshawb fawb pom Alzheimer-hom kab mob raws li ib tug correlated dementia nyob rau hauv PD [9-12]. Nrog rau kev tshawb pom ntawm -synuclein raws li ib feem tseem ceeb ntawm Lewy lub cev, Lewy neurites, thiab lwm yam lesion hom [13] thiab tom qab kev taw qhia ntawm -synuclein immunohistochemistry, cov dej ntws, thiab ntau cov kev tshawb fawb nyiam cortical Lewy pathology ua lub ntsiab (thiab yuav luag. ib leeg) neuropathological sib cuam tshuam ntawm kev paub tsis meej hauv PD. Txawm li cas los xij, nyob rau hauv kaum xyoo dhau los, ntau qhov kev tshawb fawb clincopathological tsis tu ncua qhia tias kev sib koom ua ke ntawm Alzheimer's pathology yog cuam tshuam nrog kev paub tsis meej hauv PD, ob qho tib si ntawm kev pheej hmoo thiab lub sij hawm luv luv los ntawm kab mob pib mus rau kev loj hlob ntawm dementia. Tag nrho cov kev tshawb fawb no tau raug tshuaj xyuas tas li [2, 3] thiab tau sau tseg hauv Table 1 [9–32]. Hauv luv luv, cov kev tshawb fawb loj tau pom tias, dhau li ntawm cortical Lewy-type pathology, plaque pathology yog ib qho kev txiav txim siab ntawm kev paub tsis meej hauv PD raws li A deposition yog txuam nrog kev pheej hmoo thiab lub sij hawm ntawm kev tsim dementia [22, 28, 29] thiab nrog cov kab mob ntev. [30]. Lwm tus tau txheeb xyuas tau pathology ua tus txiav txim siab ntawm kev nce mus rau dementia [32]. Cov kev tsis sib xws no raws li lub luag haujlwm tseem ceeb ntawm A lossis tau feem ntau yog qhov tshwm sim ntawm kev sib txawv ntawm cov txheej txheem (piv txwv li, suav nrog txhua daim ntawv A plaque, xws li diffuse thiab mature plaques [25, 27], vs. tsuas yog accounting neuritic plaques li A pathology. [31]).
NEUROPATHOLOGICAL EVIDENCE OF CO-EXISTING LEWY-HOM LESIONS IN ALZHEIMER'S DISEASE
Zoo ib yam li kev sib koom ua ke ntawm AD-type pathology hauv PD, Lewy-type pathology kuj tau kawm dav hauv AD. Interestingly, kev sib raug zoo ntawm Lewy pathology thiab AD nyiam cov kev txaus siab ntawm cov neeg soj ntsuam ua ntej qhov tseeb nrhiav tau ntawm ib tug Lewy pathology nyob rau hauv AD, txij li thaum kev tshawb fawb ntawm lub thiaj li hu ua nonamyloid tivthaiv ntawm plaques (NACP) [33] pib ntev ua ntej kev txheeb xyuas ntawm alpha- synuclein raws li lub ntsiab lus tseem ceeb ntawm Lewy lub cev [13]. Tom qab ntawd, ntau qhov kev tshawb fawb tau pom zoo tias ob qho tib si nyob rau hauv qhov kev txiav txim ntawm caj ces AD (xws li hauv PSEN1 tsev neeg AD thiab Down's Syndrome) Lewy pathology muaj ntau, tshwj xeeb tshaj yog nyob rau hauv amygdala, tab sis kuj nyob rau hauv lub olfactory noob, raws li summarized nyob rau hauv Table 2 [ 34–38] ib.
SUMMARY OF CO-PATHOLOGY IN PARKINSON'S DISEASE THIAB ALZHEIMER'S DISEASE
Kev sib koom ua ke ntawm Alzheimer's thiab Lewy pathologies hauv cov qauv xws li amygdala thiab olfactory noob, uas feem ntau cuam tshuam rau ob qho tib si (piv txwv li, PD thiab AD) yog kev tshawb fawb xav tau, thiab, raws li tau hais los saum no ntawm Alzheimer's thiab Lewy pathologies, Nws yog nyob rau hauv kev ua raws li kev sim cov pov thawj txhawb nqa ntawm pathological synergism. Yog li, cov proteins no muaj peev xwm hla cov noob thiab txhawb kev sib sau ua ke [39], feem ntau tej zaum tsis yog nyob rau hauv tag nrho cov xwm txheej, tab sis tshwj xeeb tshaj yog thaum muaj qee hom protein ntau tam sim no [40]. Thaum cov kev sim ua haujlwm no tsis pub dawb rau kev thuam (feem ntau hais txog qhov twg lawv tuaj yeem txhais tau li cas rau tib neeg thiab kab mob), lawv muab lub hauv paus rau kev tshawb fawb ntxiv kom nkag siab tias cov proteins no tsim cov kab mob sib xyaw ua ke thiab, thaum kawg sim tshuaj tiv thaiv tshwj xeeb. - cov protein-aggregation agents. Kev sib tham ntawm cov kev tshawb fawb kev sim no dhau ntawm qhov kev tshuaj xyuas no thiab peb xa mus rau cov kev tshuaj xyuas luam tawm lwm qhov [3].
NEUROPATHOLOGICAL EVIDENCE SYNAPTIC DYSFUNCTION hauv PD thiab AD
Synaptic dysfunction yog ib tug tshiab neeg uas ua ntawv nyob rau hauv lub teb txij li thaum nws tsis yog raws li yooj yim soj ntsuam raws li cov protein aggregation, uas immunohistochemistry muab ib tug robust cuab tam, txawm tias tsis muaj kev txwv.
Lewy lub cev tsis zoo tuaj yeem suav hais tias yog ib qho kev kho mob spectrum encompassing PD, PD-dementia (PDD), thiab dementia nrog Lewy lub cev (DLB), es tsis yog ib pawg ntawm cov xwm txheej tiag tiag. Thoob plaws qhov spectrum no, kev siv cov txuj ci tsis siv lub teeb pom kev zoo tau tso cai rau kev nkag siab thiab xaiv kev tshawb pom ntawm presynaptic-synuclein aggregates thiab pom thiab pom ib nrab ntawm cov kab mob post-synaptic dendritic spines. Piv txwv li, hauv kev tshawb fawb siv cov ntaub so ntswg paraffin-embedded (PET) blot thiab protein aggregate filtration (PAF) assay, Kramer thiab Schulz-Schaeffer tau soj ntsuam nrog PET blot ib qho loj ntawm cov me me-synuclein aggregates, uas, siv lub PAF kev soj ntsuam, feem ntau pom muaj nyob rau hauv presynaptic terminals. Qhov kev tshawb pom no tau pom los ntawm qhov yuav luag tag ntawm cov kab mob postsynaptic dendritic spines, qhov sib txawv ntawm qhov me me ntawm cortical Lewy lub cev, tshwj xeeb tshaj yog piv rau qhov hnyav ntawm kev paub tsis meej pom hauv PDD thiab DLB [41]. Raws li, cov kws sau ntawv no tau npaj cov presynaptic-synuclein aggregates thiab poob ntawm dendritic spines raws li cov xwm txheej tseem ceeb rau neurodegeneration hauv Lewy-txog kev mob [41, 42].
Kuj tseem tsom mus rau cov qauv ntawm DLB rooj plaub, ColomCadena thiab cov neeg ua haujlwm ua haujlwm tau siv cov txheej txheem microscopy hu ua array tomography (uas muab cov ntaub so ntswg ultrathin nrog immunofluorescence kom pom thiab ntsuas cov qauv me me xws li cov synapses) txhawm rau ntsuas presynaptic phosphorylated - -synuclein hauv lub cingulate cortex thiab striatum los ntawm 5 DLB rooj plaub thiab muab piv rau 5 AD thiab 5 tswj rooj plaub. Cov kws sau ntawv no pom tias 19% mus rau 25% ntawm phosphorylated-synuclein aggregates nyob rau hauv presynaptic terminals nrog synaptic terminals colocalizing nrog cov me me aggregates loj dua terminals tsis muaj xws li aggregates. Kuj tseem muaj gradient nyob rau hauv lub xub ntiag ntawm phosphorylated synaptic-synuclein aggregates, nrog rau lawv cov muaj ntau dua presynaptically qhia lub luag hauj lwm tseem ceeb rau lub presynaptic compartment [43].
Lwm cov kws sau ntawv tau tsom mus soj ntsuam lwm yam kev hloov pauv xws li kev hloov pauv ntawm lub zog tsis zoo, thiab oxidative thiab endoplasmic reticulum kev nyuaj siab puas tsuaj hauv preclinical PD siv kev kawm txog qhov xwm txheej Lewy lub cev [44]. Thaum kawg, nws tseem yog ib qho teeb meem ntawm kev sib cav txog qhov twg levodopa cuam tshuam rau kev ua haujlwm tsis zoo hauv PD, raws li ntau xyoo lawm tau ua kev soj ntsuam txhawb kev xav tias levodopa muaj teeb meem [45], thaum lwm tus tsis muaj [46].
Synaptic dysfunction kuj tseem suav nrog hauv pathophysiology ntawm AD. Nyob rau hauv cov hlab ntsha no, kev poob ntawm dendritic spines tau cuam tshuam nrog kev poob ntawm synaptic muaj nuj nqi [47-49]. Intriguingly, A, ob qho tib si nyob rau hauv nws cov insoluble (loj aggregates, filaments) thiab nws soluble (oligomers) cov ntaub ntawv, tau raug pom tias ua ntej thiab ua rau tsis ua hauj lwm ntawm dendritic spines nyob rau hauv kev sim thiab pathological kev tshawb fawb los ntawm ntau yam mechanisms xws li txo qis kev tsim, stability, thiab plasticity (inhibited long-term potentiation thiab txhim khu kev nyuaj siab ntev), mus rau qhov txawv txav ntawm synaptic scaffold proteins thiab impaired organelle thauj [50–56]. Tau hyperphosphorylation thiab microglia activation, uas raws li amyloid cascade hypothesis yog cov xwm txheej thib ob rau A pathology, tshwm sim los ua rau cov txha caj qaum tsis ua haujlwm hauv AD thiab [57]. Tsis ntev los no postsynaptic protein neurogranin txo qis hauv cov ntaub so ntswg hauv hlwb hauv AD [58].
Yog li ntawd, synaptic dysfunction nyob rau hauv PD, DLB, thiab AD, zoo li yog lub hom phiaj txaus nyiam ob qho tib si rau kev txhim kho kev paub txog kab mob mechanisms thiab tsim kho tshiab, txij li khaws cia synaptic spines tau nyob rau hauv lem txuas rau resilience tiv thaiv neurodegeneration [59]. Yog hais tias lub synaptic tsis ua hauj lwm hypothesis tuav, nws yuav theoretically muaj peev xwm rov qab los ntawm synaptic dysfunction. Txawm li cas los xij, tsis zoo li A thiab tau pathologies, nws qhov kev ntsuam xyuas neuropathologically tsis ncaj nraim, vim qhov no yuav tsum tau hais txog cov txheej txheem zoo li no. Nyob rau hauv cov nqe lus ntawm biomarkers (saib cov tshooj tom ntej) nws yog controversial seb puas muaj biomarkers (xws li A, tau, thiab -synuclein) yuav siv tau raws li indirect indicators of synaptic dysfunction los yog ntau cov cim tshwj xeeb (raws li tsim nyog synaptic proteins) yuav tsum tau siv. Yog li, synaptic dysfunction rau hnub no tseem tab tom tshawb nrhiav thiab tos cov kev tshawb fawb ntxiv, ob qho tib si neuropathologically thiab nrog biomarkers, tshwj xeeb tshaj yog nyob rau hauv cov nqe lus ntawm qhov zoo sib xws uas synaptic dysfunction tej zaum yuav muaj ntawm PD thiab AD.
BIOMARKER EVIDENCE OF PROTEINOPATHY THIAB SYNAPTIC DYSFUNCTION hauv PD
Ib qho ntawm lub hom phiaj tseem ceeb ntawm kev tshawb fawb hauv biomarkers hauv cov kab mob neurodegenerative xws li PD thiab AD yog kom tau txais cov ntaub ntawv hais txog cov kab mob neuropathology hauv vivo thaum ntxov ntawm cov txheej txheem kab mob uas tsis yog cov kev ntsuam xyuas tom qab kev tuag ntawm cov neuropathological, uas feem ntau muab cov ntaub ntawv hais txog qhov kawg- kab mob theem. Muaj ntau ntau hom thiab qhov chaw ntawm biomarkers rau ob qho tib si PD thiab AD, tab sis cov uas feem ntau cuam tshuam ncaj qha (lossis tsawg kawg tsom ntawm kev xav txog) cov kab mob hauv qab yog CSF thiab positron emission tomography (PET) biomarkers.
Hauv PD qhov kev xaiv pom tseeb xws li CSF lossis PET marker yog -synuclein. Tshaj li kaum xyoo dhau los cov kev tshawb fawb ntawm cov qib sib txawv -synuclein hom hauv CSF (feem ntau tag nrho thiab oligomeric) tau nce sai heev, txawm hais tias muaj qhov tsis sib xws, feem ntau yuav muaj feem cuam tshuam nrog ntau yam kev ntsuas ua ntej thiab kev txheeb xyuas. Txawm li cas los xij, tag nrho cov qauv yog tias CSF tag nrho-synuclein qib qis qis hauv PD thiab lwm yam synucleinopathies vs. tswj thiab lwm yam neurodegenerative mob [60, 61], nrog qhov sib txawv tshwm sim nrog CSF qib ntawm oligomeric-synuclein [62].
Txawm li cas los xij, qhov kev txhais ntawm CSF cov cim zoo li nyuaj rau cov ntsiab lus ntawm PD ntsig txog kev paub tsis meej. Yog li, ob peb txoj kev tshawb fawb tau pom tias CSF qib ntawm oligomeric-synuclein kuj zoo li nce hauv PDD thiab DLB [63, 64] (uas yog, ua raws li nws cov qauv raws li kev kuaj mob), tab sis CSF tag nrho-synuclein tau pom qhov tsis sib haum xeeb, nrog ntau qhov kev tshawb fawb hla ntu thiab ntev tau pom tias qhov siab (es tsis txhob qis) CSF tag nrho -synuclein tej zaum yuav muaj feem cuam tshuam txog kev puas hlwb [64–66]. Tag nrho cov kev tshawb pom no tau ua rau kev xav tias tsis tshua muaj CSF tag nrho -synuclein tej zaum yuav yog ib qho kev kuaj mob hauv qhov chaw ntawm ob qho tib si sequestration ntawm -synuclein nyob rau hauv lub intraneuronal aggregates, los yog ib tug compensatory reuptake ntawm cov protein kom tswj lub synaptic homeostasis. Conversely, raws li tus kab mob no zuj zus mus thiab muaj ntau dua neuronal puas thiab cell tuag, cov theem yuav nce vim yog cov proteins los ntawm qhov chaw intracellular mus rau CSF.
Qhov no yuav cuam tshuam li cas rau CSF qib ntawm AD-related proteins (tau thiab A) hauv PD tsis ncaj nraim. CSF tag nrho-synuclein tau tshaj tawm tias muaj kev sib raug zoo nrog CSF A thiab CSF tau qib [63, 66], tab sis qis CSF A tau raug cuam tshuam nrog cov txiaj ntsig tsis zoo [67-69], qhov CSF tau tau tshaj tawm tias yog Txawm li cas los xij lossis qis [63] nyob rau hauv cov kab mob thaum ntxov, tab sis nce nyob rau hauv ib feem ntawm cov kab mob PDD lig [70, 71]. Yog li ntawd, nyob rau hauv PD qis CSF A qib, xws li hauv AD, yuav cuam tshuam txog kev sequestration ntawm A nyob rau hauv extracellular parenchymal A deposits (senile plaques), thaum CSF tag nrho-synuclein theem yuav muaj xws li los ntawm qis mus rau nce paralleling dab tsi tshwm sim nrog CSF tau thiab xav txog kev nce neuronal. poob.
Xwb, tag nrho cov qauv no thiab kev sib raug zoo yuav tsis cuam tshuam nrog kev sib sau thiab tso tawm ntawm cov proteins no thiab lawv kev lag luam los ntawm qhov chaw sab hauv lossis sab nraud mus rau CSF, thiab zoo li cuam tshuam lwm cov txheej txheem, piv txwv li, synaptic tsis ua haujlwm, raws li tau hais dhau los. Txawm li cas los xij, qhov kev xav no yuav raug sib tw los ntawm kev tshawb fawb PET marker, uas muaj thiab txhim khu kev qha rau A [72] thiab tau [73], tab sis tseem tsis tau muaj rau -synuclein. Li no, rau hnub tim cov ntaub ntawv luam tawm ntawm kev tshawb fawb ntawm A imaging nyob rau hauv PD thiab DLB muaj ranged los ntawm negligible uptake nyob rau hauv PD thiab nruab nrab nce binding nyob rau hauv DLB [74, 75] mus rau ib tug ntau yam uas qhia ib tug correlation ntawm A duab thiab CSF A theem longitudinally nrog kev txawj ntse tshwm sim. hauv PD [76, 77]. Tsis ntev los no, cov ntaub ntawv zoo sib xws tau tshwm sim rau tau hauv PD thiab DLB hauv ob txoj kev tshawb fawb ywj pheej, txawm hais tias tau PET uptake cuam tshuam nrog amyloid imaging tsuas yog hauv ib qho ntawm cov kev tshawb fawb thiab tsis yog lwm yam [78, 79]. Yog li, yog tias cov duab molecular ntawm A thiab tau qhia anatomically tias muaj cov kab mob A thiab tau nyob rau hauv lub hlwb ntawm PD thiab DLB cov neeg mob thiab PET thiab CSF cov kev tshawb pom muaj kev sib raug zoo, nws yog qhov tsim nyog xav tias CSF thiab PET A thiab tau cov cim tau cuam tshuam. , tsawg kawg ib nrab, lub hauv paus pathology. Ob peb tsab ntawv ceeb toom ntawm kev tshawb pom kev tuag hauv cov neeg mob, uas tau dhau los ua CSF lossis PET cov kev tshawb fawb, kuj tseem yuav txhawb nqa qhov kev xav no [68, 80, 81], tab sis kev ceev faj tseem xav tau nrog tau imaging, raws li daim ntawv tshaj tawm kev txiav txim siab tsis ntev los no tau pom tias muaj kev tawm tsam. -target binding (neuromelanin, choroid plexus, hemorrhages) rau tau PET tracer 18F-AV-1451 [82].
Hauv cov ntsiab lus, txog hnub tim cov kev tshawb fawb CSF thiab PET tau tshaj tawm tag nrho hauv kev ua raws li cov kev tshawb fawb neuropathological tau hais los saum no hauv qhov feem ntau ntawm cov neeg mob PD muaj kev sib koom ua ke Lewy thiab Alzheimer pathologies, thiab cov chaw kho mob cuam tshuam nrog kev paub tsis meej.
Qhov no yoojyim qhib cov lus nug ntawm cov cim tshwj xeeb ntawm kev ua haujlwm tsis zoo hauv PD. Hauv cheeb tsam no, cov pov thawj muaj tsawg heev, nrog rau cov ntaub ntawv muaj nyob rau niaj hnub no los ntawm proteomic mus kom ze thiab kev xav-tsav kev tshawb fawb [83–86]. Hauv CSF proteomic txoj kev tshawb fawb synaptic cov cim, ntawm lwm cov proteins, tau kuaj pom qhov sib txawv ntawm ntau hom atypical parkinsonism, PD, thiab tswj [83]. Ib qho kev soj ntsuam tom qab ntawm 27 cov kev tshawb fawb proteomic, uas pom tag nrho ntawm 500 qhov sib txawv qhia cov proteins, xaus lus tias presynaptic proteins koom nrog hauv vesicle membrane fusion xws li SNAP25 tuaj yeem siv los ua biomarkers rau PD [84]. Hauv cov hlab ntsha no, kev tshawb fawb tom qab kev tuag tau pom cov koom haum ntawm kev paub txog kev poob qis hauv DLB thiab AD nrog qib ntawm Rab3A nyob rau hauv inferior parietal lobe thiab cov SNAP25 hauv prefrontal cortex, feem [85]. Tib pab pawg tshawb fawb tsis ntev los no tau tshaj tawm txoj kev tshawb fawb ntawm cov proteins no hauv CSF thiab pom tau nce CSF qib ntawm SNAP25 thiab neurogranin, uas cuam tshuam nrog kev paub thiab lub cev muaj zog cov tsos mob hnyav [86].
Cov ntsiab lus ntawm kev tshaj tawm rhiab heev thiab qhov tshwj xeeb ntawm -synuclein cov cim muaj nyob rau hauv Cov Lus Qhia Ntxiv 1.
BIOMARKER pov thawj ntawm kev sib koom ua ke PROTEINOPATHY thiab SYNAPTIC DYSFUNCTION AD
Nyob rau hauv AD raws li nyob rau hauv PD cov ntaub ntawv pov thawj ntawm biomarkers ntawm -synuclein pathology yog qhov tseeb txwv rau CSF cov kev tshawb fawb, txij li thaum, raws li twb tau tham lawm tseem tsis tau muaj ib tug validated PET sojntsuam tshwj xeeb rau -synuclein. Cov kev tshawb fawb muaj nyob rau hnub no kuj tau pom qhov tsis sib xws txog CSF tag nrho-synuclein. Yog li, qee qhov kev tshawb fawb pom tsis muaj qhov sib txawv hauv CSF tag nrho-synuclein ntawm synucleinopathies (PD thiab DLB) thiab AD [87–89], whereas lwm tus tau pom tias muaj kev sib koom ua ke ntawm qis CSF tag nrho-synuclein qib hauv AD thiab cov qhab nia ntawm cov kev ntsuam xyuas thoob ntiaj teb xws li raws li qhov kev xeem me me hauv lub xeev kev xav, tawm tswv yim tias nws tau tsim ib qho kev qhia dav dav ntawm synapse poob [8]. Txawm li cas los xij, ntau cov ntaub ntawv tshaj tawm tau taw qhia txog kev nce qib ntawm CSF tag nrho --synuclein hauv AD [90–93], txuas nws mus rau kev ua phem rau neurodegeneration hauv tus mob no, zoo ib yam li qib siab ntawm CSF tau thiab {{12. }} proteins nyob rau hauv qhov teeb meem ntawm aggressive neuronal tuag raws li pom nyob rau hauv Creutzfeldt-Jakob kab mob los yog AD nws tus kheej.
Hais txog CSF cov cim qhia ntawm synaptic dysfunction hauv AD, synaptic proteins ib nrab sib tshooj nrog cov uas tau hais los saum no txog PD tau raug soj ntsuam ntau hauv AD ua ntej lawv raug tshawb xyuas hauv PD. Raws li, ntau qhov kev tshawb fawb tau tshaj tawm txog CSF qib ntawm neurogranin [94-96], synaptotagmin [97], thiab contactin [98] hauv AD ob qho tib si hauv nws qhov chaw kho mob thiab nws theem prodromal raws li kev xav los ntawm kev paub tsis meej me ntsis nrog cov pov thawj lom ntawm AD. (uas yog, CSF tau thiab A qhov txawv txav), qhia tias cov no yuav muaj kev ywj pheej thiab ua tiav biomarkers ntawm AD [99–101] Raws li, kev tshuaj ntsuam xyuas tsis ntev los no tau pom zoo suav nrog neurogranin hauv vaj huam sib luag ntawm AD biomarkers [102]. Txawm li cas los xij, muaj cov teeb meem tseem ceeb hais txog qhov tshwj xeeb, txij li thaum tshwm sim nrog cov proteins xws li tau, nce CSF qib ntawm neurogranin tsuas yog cuam tshuam txog kev puas hlwb hauv cov mob hnyav xws li kab mob Creutzfeldt-Jakob [103].
Raws li rau synaptic CSF makers nyob rau hauv PD, tsis ntev los no CSF theem ntawm neurogranin tau raug soj ntsuam nyob rau hauv parkinsonian mob, nrog rau kev tshawb pom tias cov no tau txo nyob rau hauv PD, PDD, MSA, thiab PSP txheeb ze rau AD thiab tswj, tsis correlated nrog lub cev muaj zog los yog kev txawj ntse ntsuas, txawm [104]. Los ntawm qhov sib txawv, nyob rau hauv lwm txoj kev tshawb fawb nce neurogranin CSF qib mirrored txo CSF Ain PD thiab nyob rau hauv cov ntaub ntawv no, ib tug tseem ceeb correlation nrog cognition (raws li ntsuas los ntawm MMSE) tau tshaj tawm [105]. Yog li xav tau kev tshawb fawb ntau ntxiv los qhia txog cov kev sib koom ua ke ntawm cov cim synaptic hauv degenerative parkinsonian mob.
Tam sim no, cov cim no tab tom tshawb nrhiav tsis yog hauv CSF nkaus xwb tab sis kuj tseem nyob hauv cov ntshav exosomes, uas yuav muab cov khoom siv tau yooj yim dua rau CSF [106].
Ib qho kev nthuav dav ntawm kev tshaj tawm rhiab heev thiab tshwj xeeb ntawm τ thiab A cov cim tau sau tseg hauv Cov Lus Ntxiv 1.
Lwm tus BIOMARKERS hauv AD thiab PD Kev Tshawb Fawb
Txawm hais tias nws tsis yog nyob rau hauv qhov kev tshuaj xyuas no, qhov kev txaus siab ntau ntxiv hauv neurofilaments thiab cov cim ntawm neuroinflammation raws li biomarkers hauv ob qho tib si AD thiab PD yuav tsum tau hais. Neurofilament tau raug txheeb xyuas tias yog tus cim ntawm tus kab mob kev loj hlob lossis tus cim prognostic nyob rau hauv ntau lub paj hlwb los ntawm ntau yam sclerosis [107] mus rau amyotrophic lateral sclerosis [108] thiab, tseem ceeb kuj nyob rau hauv ob qho tib si AD [109] thiab PD [110]. Ib qho kev ua tiav hauv kev tshawb fawb ntawm biomarker no tau ua qauv qhia tias nws cov qib hauv plasma cuam tshuam nrog cov neeg hauv CSF [111], ua rau nws siv tau ntau dua biomarker. Raws li cov cim ntawm neuroinflammation, muaj kev tshawb fawb ntawm ob qho tib si neuronal-specific (YKL-40 [112]) thiab cov cim tsis tshwj xeeb (cytokines [113]) raws li kev kuaj mob thiab kev nce qib biomarkers hauv AD thiab PD.
Cov lus xaus
Muaj cov pov thawj txaus ntseeg tias PD thiab AD qhia txog cov kab mob neuropathological hauv A thiab tau cov kab mob ntawm Alzheimer hom yog muaj nyob rau hauv PD thiab, vice versa, -synuclein Lewy-type aggregates yog nquag tshawb pom hauv AD. Niaj hnub nimno cov txheej txheem tsis sib haum xeeb kov yeej cov kev txwv ntawm cov txheej txheem immunohistochemical niaj hnub tau cog lus tias yuav coj peb txoj kev paub ntxiv ntawm qhov cuam tshuam ntawm cov kab mob sib txuas nrog cov proteinaceous aggregates tshaj li cov neurons 'soma, nqis mus rau lawv cov presynaptic thiab postsynaptic terminals, nrog rau cov cuab yeej siv tau thiab txawm tias yav tom ntej kev cuam tshuam.
Ib qho kev sib tw loj dua yog txhais cov kev paub no rau lub tsev kho mob. CSF thiab PET cov cim ntawm A thiab tau ua haujlwm zoo hauv AD, tab sis lawv cov neeg sib tw hauv PD yog nyob deb ntawm kev ntseeg tau sib npaug, nrog cov kev cog lus tshiab yog cov txheej txheem aggregometry xws li lub sijhawm tiag tiag quaking-induced conversion (RT-QuIC Ib.) [114]. Nyob rau hauv cov nqe lus ntawm PET cov cim, ntxiv rau qhov tseeb tias tsis muaj PET sojntsuam muaj rau -synuclein tsis tau, AD PET cov cim muaj ntau yam los ntawm cov pov thawj zoo ib yam ntawm lawv qhov tshwj xeeb (amyloid imaging) mus rau qhov tsis paub tseeb ntawm lawv qhov kev ntseeg siab vim yog kev sib txuas ntawm lub hom phiaj (tau duab). CSF synaptic markers yog qhov txaus nyiam, tab sis cov pov thawj tseem tsis tshua muaj thiab feem ntau tej zaum cov no yuav yog cov cim tsis tshwj xeeb ntawm kev kis kab mob. Rau tag nrho cov CSF thiab PET cov cim no, ib tus yuav tsum nco ntsoov tias 'cov cim tsis yog ib txwm tsim', thiab yog li yuav tsum tau ceev faj thaum txhais cov koom haum ua qhov laj thawj.
Hauv cov ntsiab lus thiab rov qab los rau cov lus nug uas tau tsa hauv lub npe ntawm qhov kev tshuaj xyuas no (Dab tsi yog qhov cuam tshuam zoo sib xws ntawm PD thiab AD? Cov protein aggregates? synaptic dysfunction? lossis ob qho tib si?), los ntawm neuropathological point of view protein aggregates muaj ob qho tib si ntawm soma thiab synapse. Yog li, ob peb CSF thiab PET biomarkers tuaj yeem ntes cov sib txawv ntawm cov protein cuam tshuam txog neurodegeneration. Tshwj xeeb tshaj yog, CSF -synuclein, tau, thiab A qib yuav muaj kev cuam tshuam ib sab ntawm cov protein sib sau ua ke thiab tseem muaj cov feem cuam tshuam ntawm cov proteins ntawm qib synapse (Table 3).
TXOJ CAI
YC lub tsev kawm ntawv tau txais kev txhawb nqa los ntawm CERCA Program ntawm Generalitat de Catalunya (Barcelona, Catalonia). TR tau txais kev txhawb nqa los ntawm kev tshawb fawb nyiaj txiag los ntawm Karin & Sten Mortstedt CBD Solutions (grant code: 512385). Qhov kev tshawb fawb no yog ib feem txhawb nqa los ntawm National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit hauv Dementia raws li University College London Tsev Kho Mob (UCLH), University College London (UCL). Cov kev xav tau nthuav tawm yog cov neeg sau ntawv thiab tsis tas yuav yog cov ntawm NHS, NIHR, lossis Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv.
Kev tsis sib haum xeeb ntawm kev txaus siab
Cov neeg sau ntawv tsis muaj teeb meem ntawm kev txaus siab los qhia.
SUPPLEMENTARY KHOOM
Cov khoom siv ntxiv muaj nyob rau hauv hluav taws xob ntawm tsab xov xwm no: https://dx.doi.org/ 10.3233/JPD-202323.
REFERENCES
[1] Aarsland D, Andersen K, Larsen JP, Lolk A, KraghSørensen P (2003) Prevalence and features of dementia in Parkinson's disease: Ib 8- xyoo kawm ntawv yav tom ntej. Arch Neurol 60, 387-392.
[2] Irwin DJ, Lee VM, Trojanowski JQ (2013) Parkinson's disease dementia: Convergence of a-synuclein, tau, and amyloid-ß pathologies. Nat Rev Neurosci 14, 626-636.
[3] Compta Y, Parkkinen L, Kempster P, Selikhova M, Lashley T, Holton JL, Lees AJ, Revesz T (2014) Qhov tseem ceeb ntawm a-synuclein, amyloid- thiab tau pathologies hauv Parkinson tus kab mob kev loj hlob thiab cuam tshuam txog kev dementia. Neurodegener Dis 13, 154-156.
[4] Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM, Iwatsubo T, Trojanowski JQ (1998) Lewy lub cev muaj cov hloov pauv alpha-synuclein hauv hlwb ntawm ntau tsev neeg Alzheimer's kab mob cov neeg mob uas muaj kev hloov pauv hauv presenilin thiab amyloid precursor protein noob. Am J Pathol 153, 1365-1370.
[5] Hamilton RL (2000) Lewy lub cev hauv Alzheimer's kab mob: Kev tshuaj xyuas neuropathological ntawm 145 tus neeg mob siv alpha-synuclein immunohistochemistry. Lub hlwb Pathol 10, 378-384.
[6] Otto M, Wiltfang J, Tumani H, Zerr I, Lantsch M, Kornhuber J, Weber T, Kretzschmar HA, Poser S (1997) Nce qib ntawm tau protein nyob rau hauv cov kua cerebrospinal ntawm cov neeg mob Creutzfeldt-Jakob. Neurosci Lett 225, 210-212.
[7] Zahs KR, Ashe KH (2013) -Amyloid oligomers in aging and Alzheimer's disease. Pem Hauv Ntej Aging Neurosci 5, 28.
[8] Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmechelen E, Blennow K, Zetterberg H (2009) Cerebrospinal fluid alpha-synuclein hauv neurodegenerative ntshawv siab-ib qho cim ntawm synapse poob? Neurosci Lett 450, 332-335.
[9] Hakim AM, Mathieson G (1979) Dementia in Parkinson's disease: Kev tshawb fawb neuropathological. Neurology 29, 1209- 1214.
[10] Boller F, Mitzutani T, Roessman U, Gambetti P (1980) Parkinson disease, dementia, thiab Alzheimer disease: Clinicopathological correlations. Ann Neurol 7, 329-335.
[11] Jendroska K, Lees AJ, Poewe W, Daniel SE (1996) Amyloid beta-peptide thiab dementia ntawm Parkinson's disease. Mov Disord 11, 647-53.
[12] Mattila PM, Roytt ¨ M, Torikka H, Dickson DW, Rinne JO ¨ (1998) Cortical Lewy lub cev thiab Alzheimer-hom hloov pauv hauv cov neeg mob Parkinson's disease. Acta Neuropathol 95, 576-582.
[13] Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein nyob rau hauv filamentous inclusions ntawm Lewy lub cev los ntawm Parkinson tus kab mob thiab dementia nrog Lewy lub cev. Proc Natl Acad Sci USA 95, 6469-6473.
[14] Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M (2000) Alpha-synuclein-immunoreactive cortical Lewy lub cev yog txuam nrog kev paub tsis meej hauv Parkinson tus kab mob. Acta Neuropathol 100, 285-290.
[15] Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM, Clark CM, Glosser G, Stern MB, Gollomp SM, Arnold SE (2000) Alpha-synuclein cortical Lewy lub cev cuam tshuam nrog dementia hauv Parkinson's disease . Neurology 54, 1916-1921.
For more information:1950477648nn@gmail.com
