帕金森病伴認(rèn)知障礙的多模態(tài)MR研究進(jìn)展課件

1、 帕金森病伴認(rèn)知障礙的多模態(tài)MR研究進(jìn)展 Advance of multi modality MR in Parkinsons disease with cognitive impairment概念流行病學(xué)病因發(fā)病機(jī)制神經(jīng)病理臨床表現(xiàn)藥物治療多模態(tài)MR在認(rèn)知障礙中的應(yīng)用 目錄Content 概念Conception帕金森病（Parkinsons disease，PD），又稱震顫麻痹（Paralysis agitans），由英國醫(yī)師James Parkinson（1817年）首先描述，是一種中老年人常見的中樞神經(jīng)系統(tǒng)變性疾病，以中腦黑質(zhì)多巴胺能神經(jīng)元大量變性丟失和路易小體（Lewy body）形

2、成為病理特點(diǎn)，以靜止性震顫、肌強(qiáng)直、運(yùn)動(dòng)遲緩和慌張步態(tài)及非運(yùn)動(dòng)癥狀為臨床特征。認(rèn)知障礙：指定向力、記憶力、計(jì)算力及智力下降，通過簡易智能精神狀態(tài)檢查量表（MMSE）協(xié)助診斷。分類：帕金森病合并輕度認(rèn)知損害（PD-MCI）和帕金森病癡呆（PDD）。 流行病學(xué)Epidemiology國外文獻(xiàn)報(bào)道，60歲以上的人發(fā)病率為約2%。1 隨著年齡的增加帕金森病的發(fā)病率逐漸上升。據(jù)國外流行病學(xué)調(diào)查，PD患者中40會(huì)伴發(fā)認(rèn)知功能障礙。2全球不同地區(qū)間帕金森病發(fā)病率無明顯差異：歐洲全人群發(fā)病率為922/10萬人年、北美洲全人群發(fā)病率為1113/10萬人年、亞洲全人群發(fā)病率為1.5 17.0/10萬人年。3病因E

3、tiologic factors年齡老化環(huán)境因素遺傳易患性家族遺傳性發(fā)病機(jī)制Pathogenesis帕金森病是一種中老年人常見的中樞神經(jīng)系統(tǒng)變性疾病，發(fā)病機(jī)制尚未明確。目前較認(rèn)可的有遺傳因素、環(huán)境因素、蛋白質(zhì)表達(dá)異常、氧化應(yīng)激、鐵代謝異常、泛素-蛋白酶體系統(tǒng)及自噬等相關(guān)。PD患者的認(rèn)知功能損害在病理表現(xiàn)上主要與邊緣系統(tǒng)包括（海馬、內(nèi)嗅皮質(zhì)、扣帶回、杏仁核、前核、丘腦、乳頭體、隔區(qū))神經(jīng)變性密切相關(guān)。記憶損害與海馬萎縮有關(guān)，注意力不能保持則與額回萎縮有關(guān)。NeuropathologyDauer W, et al .Neuron, 2003, 39(6):889-909. (A)It is com

4、posed of dopaminergic neurons whose cell bodies are located in the substantia nigra pars compacta (SNpc; see arrows). These neurons project (thick solid red lines) to the basal ganglia and synapse in the striatum . (B)In Parkinsons disease, the nigrostriatal pathway degenerates.There is a marked los

5、s of dopaminergic neurons that project to the putamen (dashed line) and a much more modest loss of those that project to the caudate (thin red solid line).(C) Immunohistochemical labeling ofintraneuronal inclusions, termed Lewy bodies, in a SNpc dopaminergic neuron. 4 臨床表現(xiàn)Clinical features運(yùn)動(dòng)癥狀：靜止性震顫

6、、肌強(qiáng)直、運(yùn)動(dòng)遲緩、慌張步態(tài)等。非運(yùn)動(dòng)癥狀：認(rèn)知障礙、抑郁、幻覺、睡眠紊亂等精神方面癥狀。 藥物治療Drug Therapy左旋多巴替代治療DR激動(dòng)劑金剛烷胺單胺氧化酶B（MAO-B）抑制劑兒茶酚-氧位-甲基轉(zhuǎn)移酶（COMT）抑制劑Drug TherapyLuigi Albert .Wikipedia, July,2014. Treatment in the initial state aims to attain an optimal trade off between good management of symptoms and side effects resulting from e

7、nhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of causing the onset of dyskinesias to be retarded.多模態(tài)磁共振成像Multi Modality Magnetic Resonance Imaging 磁共振成像最主要的一個(gè)優(yōu)點(diǎn)就是它具有多種成像模態(tài)，釆用多模態(tài)

8、磁共振成像已經(jīng)成為多個(gè)研究領(lǐng)域特別是神經(jīng)、精神性疾病領(lǐng)域的一個(gè)重要研究手段。多模態(tài)MR在認(rèn)知障礙中的應(yīng)用Application of multi modality MR in cognitive impairment磁敏感加權(quán)成像（susceptibility weighted imaging，SWI）質(zhì)子磁共振波譜分析(Proton magnetic resonance spectroscopy，1H-MRS）彌散張量成像（diffusion tensor imaging，DTI）基于體素的形態(tài)學(xué)分析（voxel based morphometric，VBM）基于纖維的空間統(tǒng)計(jì)方法（trac

9、t based spatial statistics，TBSS）血氧水平依賴磁共振腦功能成像 (Blood oxygenation level dependent fMRI，BOLD-fMRI） 磁敏感加權(quán)成像（SWI）SWI利用磁場中組織局部或內(nèi)部間磁敏感差異而產(chǎn)生增強(qiáng)磁共振影像對(duì)比的一種T2脈沖序列技術(shù)，反映的是組織磁化屬性。對(duì)于顯示靜脈血管、血液成分、鈣化、鐵沉積等非常敏感?？捎糜谀X組織鐵沉積的生化及定量分析。鐵對(duì)于中樞神經(jīng)系統(tǒng)的多種功能活動(dòng)來說極其重要，在顱內(nèi)主要位于錐體外系，特別是黑質(zhì)致密部。SWI 上能夠顯示早期PD患者黑質(zhì)鐵沉積高于正常人5 。 Susceptibility We

10、ighted ImagingSWI phase values of substantia nigra of (A) control group (-0.901), (B) early PD group (0.110), and (C) intermediate/ advanced PD group (0.130).There were significant differences in phase values of nigra between control individuals and patients with early PD (all p 0.05). all values we

11、re significantly (all p 0.05) different in patients with intermediate and advanced PD.Wu S F, et al. European Review for Medical & Pharmacological Sciences, 2014, 18(18):2605-2608.ABC質(zhì)子磁共振波譜分析(1H-MRS）MRS是利用磁共振顯像和化學(xué)位移作用，檢測活體組織能量代謝、生化改變及化合物定量分析的一種無創(chuàng)性影像技術(shù)。N-乙酰天冬氨酸( NAA）是哺乳動(dòng)物神經(jīng)系統(tǒng)中普遍存在的化合物之一，NAA在腦內(nèi)幾乎全部位于

12、神經(jīng)元內(nèi)，其濃度降低反映了神經(jīng)元或軸突的破壞和缺失以及功能的異常。Cho是細(xì)胞膜磷酯代謝的一個(gè)組成成分，Cho含量增加提示有神經(jīng)膠質(zhì)細(xì)胞增生，肌酸(CR)為能量代謝產(chǎn)物，濃度相對(duì)穩(wěn)定，作為 1H-MRS研究的內(nèi)參物。通過 H-MRS測定顱內(nèi)特定部位的NAACR、CHoCR值。運(yùn)用于帕金森病伴認(rèn)知障礙的研究中，發(fā)現(xiàn)NAACR比值在枕葉減少，CHoCR值在后扣帶回增加。(a)VOI within the substantia nigra (A), basal ganglia (B), posterior cingulated (C) and occipital lobe (D). (b) Typi

13、cal spectra obtained from a healthy adult. Major peaks indicate choline (Cho), creatine (Cr) and Nacetylaspartat(NAA).The ratios of NAA and Cho in relative to Cr were used to minimize the influence of structural tissue atrophy within the VOI on the MRS results. 7 Proton Magnetic Resonance Spectrosco

14、pyNie K, et al. Parkinsonism & Related Disorders, 2012, 19(3):329334.Changes of the ratio of Cho/Cr in the posterior cingulate. Note an increase in the Cho/Cr in the posterior cingulate when compared with the healthy control. The data were presented in mean and standard deviation (SD).Magnetic Reson

15、ance SpectroscopyNie K, et al. Parkinsonism & Related Disorders, 2012, 19(3):329334.Changes of the ratio of NAA/Cr in the occipital lobe. A decrease of the NAA/Crratio was shown in PD-MCI patients. The data were presented in mean and standard deviation (SD).彌散張量成像（DTI）DTI 是在DWI 技術(shù)基礎(chǔ)上發(fā)展起來的一種新的磁共振成像技術(shù)

16、, DTI 研究近年來發(fā)展迅速，該技術(shù)能夠無創(chuàng)地顯示腦白質(zhì)纖維走行，是目前腦部退行性疾病研究熱點(diǎn)。DTI 的各向異性可由幾個(gè)指標(biāo)量化，包括FA( fractional anisotropy) 、AI( anisotropy index) ，其中FA 最為常用，反映神經(jīng)纖維的完整性等。 通過DTI發(fā)現(xiàn)帕金森病患者左側(cè)前扣帶束、胼胝體膝部結(jié)構(gòu)FA值下降，提示該區(qū)域受損，可能在帕金森病認(rèn)知功能損害的發(fā)生過程中發(fā)揮重要作用。Diffusion Tensor ImagingTable the maximum level of the body of the lateral ventricle in di

17、fferent cognitive function groups.Note: the green arrow genu; white arrow in the splenium of corpus callosum. Cognition of Parkinsons disease.Functional group; mild cognitive impairment in Parkinsons disease; Parkinsons disease dementia group.Deng bin-mei,Southern Medical University,2012.基于體素的形態(tài)學(xué)分析（

18、VBM）原理：VBM方法引入到DTI 研究中，采用SPM 軟件對(duì)各向異性指數(shù)（fractional anisotropy，F(xiàn)A） 圖和平均擴(kuò)散率（mean diffusion，MD）圖進(jìn)行體素水平的統(tǒng)計(jì)分析，最后得到全腦的差異圖，也有研究者將此稱為基于體素的分析（voxel based analysis，VBA）。主要用于測量腦灰質(zhì)密度，發(fā)現(xiàn) PD-MCI患者右顳葉、楔葉、楔前葉，眶額葉皮質(zhì)密度降低。Voxel Based MorphometricZhang J, et al. International Journal of Clinical & Experimental Medicine,

19、 2015, 8(9):15383-15392.Gray matter comparison between patients with Parkinson disease with and without mild cognitive impairment (PD-MCI versus PD-nMCI). In PD-MCI group, gray matter reductions were more widespread, including right temporal lobe, precuneus, cuneus, lingual gyrus, fusiform gyrus, or

20、bitofrontal cortex. Structural gray matter differences in the two groups showed MCI and nMCI were the two stages during the progress of the PD.9 基于纖維的空間統(tǒng)計(jì)方法（TBSS）TBSS 方法首先需構(gòu)建一組圖像的平均FA 骨架圖， 骨架圖代表被試者較大的白質(zhì)纖維束中心，然后將所有被試的FA 值投射到平均FA 骨架圖上，以確保骨架圖上每一個(gè)體素的FA 值均來自于最鄰近的白質(zhì)纖維束中心。應(yīng)用：測量腦白質(zhì)纖維束，PD-MCI 病人出現(xiàn)雙側(cè)大腦半球和胼胝體的

21、腦白質(zhì)纖維素分布異常，推測PD 病人輕度認(rèn)知功能低下腦白質(zhì)聯(lián)絡(luò)纖維異常具有相關(guān)性。Tract Based Spatial StatisticsTract-based spatial statistics results in PD-MCI patients compared with healthy controls and PD-Cu patients. Voxelwise group differences are shown in red (decreased FA). Results are overlaid on the WM skeleton (light green) and d

22、isplayed on the sagittal, coronal, and axial sections of the MNI standard brain in neurological convention (right is right) at P 0.05 FWE-corrected.Abbreviations: FA, fractional anisotropy; FWE, familywise error; PD-Cu, cognitively unimpaired PD patients; PD-MCI,PD patients with mild cognitive impai

23、rment. 10 Agosta F, et al. Human Brain Mapping,2014,35(5):1921-1929.PD 患者的腦功能通路（如中腦緣-紋狀體、皮質(zhì)-紋狀體通路）較正常人活躍性減低， 并且中腦緣-紋狀體通路中的功能缺陷可能與PD 伴非運(yùn)動(dòng)癥狀的潛在病理相關(guān)。 BOLD-fMRI根據(jù)人腦功能區(qū)被信號(hào)激活時(shí)血紅蛋白和脫氧血紅蛋白兩者之間比例發(fā)生改變,隨之產(chǎn)生局部磁共振信號(hào)的改變而進(jìn)行工作的，應(yīng)用BOLD-fMRI進(jìn)行激活研究，探測的BOLD信號(hào)可以作為腦功能區(qū)活性的直接標(biāo)志。血氧水平依賴磁共振腦功能成像 (BOLD-fMRI)Differences in the connectivity patterns of striatum in patients with Parkinsons disease. F