动物分子影像技术在帕金森病诊断研究中的运用
|
摘要
帕金森病(Parkinson’s disease,PD)是一种神经退行性疾病,在中老年群体中较为常见,危害性大,但是早期临床诊断与鉴别帕金森病、帕金森叠加综合征以及其他运动障碍性疾病有一定的困难性,因此临床前的研究显得尤为重要,利用动物分子影像技术对帕金森病模型进行活体脑部显像,能够动态观察帕金森病的形成和脑深部电刺激(DBS)治疗前后多巴胺受体的代谢及动力学变化,对帕金森病早期诊断及发病机制研究有一定的作用,当前帕金森病实验动物的脑部显像可以采用小动物PET/CT、小动物MRI和小动物SPECT进行精确诊断,通过诸多研究结果,可以明显提升诊断效率,与临床诊断结果达到高度一致性,为临床鉴别和诊断帕金森病和帕金森综合征提供数据支持。综述了近年来国内外研究者利用分子影像技术对帕金森病临床前研究的结果,展现了分子影像医学的发展趋势,对未来诊断和治疗帕金森疾病具有一定的参考价值。
Parkinson's disease(PD) is a neurodegenerative disease common in middle-aged and old people. It is difficult to diagnose and differentiate PD, Parkinson's superimposition syndrome and other motor disorders in the early stages. Therefore, preclinical research is particularly important, and animal molecular imaging are used. Imaging technology can dynamically observe the formation of Parkinson's disease and the changes of dopamine receptor metabolism and kinetics before and after deep brain stimulation(DBS) treatment in vivo. It is helpful for the early diagnosis and understanding pathogenesis of Parkinson's disease. At present, small animal PET/CT,MRI and SPECT are used for the brain imaging of Parkinson's experimental animals for accurate diagnosis. Further research is needed to significantly improve the diagnostic efficiency and achieve a high degree of consistency with clinical diagnostic results, and serves the diagnosis and differential diagnosis of Parkinson's disease and Parkinson's syndrome. This paper reviews the results of preclinical studies on Parkinson's disease using molecular imaging technology in recent years, and illustrates the development trend of imaging medicine, which has a certain reference value for the future diagnosis and treatment of Parkinson's disease.
Parkinson's disease(PD) is a neurodegenerative disease common in middle-aged and old people. It is difficult to diagnose and differentiate PD, Parkinson's superimposition syndrome and other motor disorders in the early stages. Therefore, preclinical research is particularly important, and animal molecular imaging are used. Imaging technology can dynamically observe the formation of Parkinson's disease and the changes of dopamine receptor metabolism and kinetics before and after deep brain stimulation(DBS) treatment in vivo. It is helpful for the early diagnosis and understanding pathogenesis of Parkinson's disease. At present, small animal PET/CT,MRI and SPECT are used for the brain imaging of Parkinson's experimental animals for accurate diagnosis. Further research is needed to significantly improve the diagnostic efficiency and achieve a high degree of consistency with clinical diagnostic results, and serves the diagnosis and differential diagnosis of Parkinson's disease and Parkinson's syndrome. This paper reviews the results of preclinical studies on Parkinson's disease using molecular imaging technology in recent years, and illustrates the development trend of imaging medicine, which has a certain reference value for the future diagnosis and treatment of Parkinson's disease.
引文
[1] Chen W,Xu ZM,Wang G,et al.Non-motor symptoms of Parkinson’s disease in China:a review of the literature [J].Parkinsonism Relat Disord,2012,18(5):446-452.
[2] Sun Q,Wang T,Jiang TF,et al.Effect of a leucine-rich repeat kinase 2 variant on motor and non-motor symptoms in Chinese Parkinson’s disease patients [J].Aging Dis,2016,7(3):230-236.
[3] Wang G,Huang Y,Chen W,et al.Variants in the SNCA gene associate with motor progression while variants in the MAPT gene associate with the severity of Parkinson’s disease [J].Parkinsonism Relat Disord,2016,24(3):89-94.
[4] Wang W,Wang X,Fujioka H,et al.Parkinson’s disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes [J].Nat Med,2016,22(1):54-63.
[5] Yang X,Lou Y,Liu G,et al.Microglia P2Y6 receptor is related to Parkinson’s disease through neuroinflammatory process [J].J Neuroinflammation,2017,14(1):38.
[6] Jiang QW,Wang C,Zhou Y,et al.Plasma epidermal growth factor decreased in the early stage of Parkinson’s disease [J].Aging Dis,2015,6(3):168-173.
[7] Ma J,Jiang Q,Xu J,et al.Plasma insulin-like growth factor 1 is associated with cognitive impairment in Parkinson’s disease [J].Dement Geriatr Cogn Disord,2015,39(5-6):251-256.
[8] Kang WY,Yang Q,Jiang XF,et al.Salivary DJ-1 could be an indicator of Parkinson’s disease progression [J].Front Aging Neurosci,2014,6(6):102.
[9] Chen Y,Gao C,Sun Q,et al.MicroRNA-4639 is a regulator of DJ-1 expression and a potential early diagnostic marker for Parkinson’s disease [J].Front Aging Neurosci,2017,9(7):232.
[10] Halliday G,Lees A,Stern M.Milestones in Parkinson’s disease:clinical and pathologic features [J].Mov Disord,2011,26(6):1015-1021.
[11] 王琴,张春银.小动物PET在缺血性脑血管病中的应用进展[J].中国医学影像技术,2014,30(7):1117-1120.
[12] Oh-Ici D,Wespi P,Busch J,et al.Hyperpolarized metabolic MR imaging of acute myocardial changes and recovery after ischemia-reperfusion in a small-animal mode [J].Radiology,2016,278(3):742-751.
[13] Borghammer P.Perfusion and metabolism imaging studies in Parkinson’s disease [J].Dan Med J.2012,59(6):B4466.
[14] Kang W,Chen W,Yang Q,et al.Salivary total alpha-synuclein,oligomeric alpha-synuclein and SNCA variants in Parkinson’s disease patients [J].Sci Rep,2016,6(6):28143.
[15] 冯悦,钟萌,陈跃.小动物PET/CT显像考察麻黄碱干预棕色脂肪18F-FDG摄取的研究 [J].泸州医学院学报,2015,38(4):341-343.
[16] 凌泽民,唐颖,李颖勤,等.小动物PET-CT在大鼠臂丛根性撕脱脊髓损伤的应用研究 [J].解剖学研究,2015,37(2):88-92.
[17] Huang P,Tan YY,Liu DQ,et al.Motor-symptom laterality affects acquisition in Parkinson’s disease:a cognitive and functional magnetic resonance imaging study [J].Mov Disord,2017,32(7):1047-1055.
[18] Honer M,Hengerer B,Blagoev M,et al.Comparison of [18F]FDOPA,[18F]FMT and [18F]FECNT for imaging dopaminergic neurotransmission in mice [J].Nucl Med Biol,2006,33(5):607-614.
[19] Casteels C,Vermaelen P,Nuyts J,et al.Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain[J].J Nucl Med,2006,47(11):1858-1866.
[20] Casteels C,Lauwers E,Bormans G,et al.Metabolic-dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease[J].Eur J Nucl Med Mol Imaging,2008,35(1):124-134.
[21] Sun W,Sugiyama K,Fang X,et al.Different striatal D2-like receptor function in an early stage after unilateral striatal lesion and medial forebrain bundle lesion in rats[J].Brain Res,2010,1317(4):227-235.
[22] Jang DP,Min HK,Lee SY,et al.Functional neuroimaging of the 6-OHDA lesion rat model of Parkinson’s disease[J].Neurosci Lett,2012,513(2):187-192.
[23] D?br?ssy MD,Braun F,Klein S,et al.[18F]desmethoxyfallypride as a novel PET radiotracer for quantitative in vivo dopamine D2/D3 receptor imaging in rat models of neurodegenerative diseases[J].Nucl Med Biol,2012,39(7):1077-1080.
[24] Li X,Chen Z,Tang J,et al.Synthesis and biological evaluation of 10-11C-dihydrotetrabenazine as a vesicular monoamine transporter 2 radioligand [J].Arch Pharm (Weinheim),2014,347(5):313-319.
[25] Bu L,Li R,Liu H,et al.Intrastriatal transplantation of retinal pigment epithelial cells for the treatment of Parkinson disease:in vivo longitudinal molecular imaging with18F-P3BZA PET/CT [J].Radiology,2014,272(1):174-183.
[26] Park BN,Kim JH,Lee K,et al.Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson’s disease:small animal positron emission tomography study with18F-FP-CIT [J].Eur Radiol,2015,25(5):1487-1496.
[27] Zhou X,Doorduin J,Elsinga PH.et al.Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia [J].Neuroimage,2017,157(8):209-218.
[28] Crabbé M,Van der Perren A,Weerasekera A,et al.Altered mGluR5 binding potential and glutamine concentration in the 6-OHDA rat model of acute Parkinson’s disease and levodopa-induced dyskinesia [J].Neurobiol Aging,2018,61(1):82-92.
[29] Ando K,Obayashi S,Nagai Y,et al.PET analysis of dopaminergic neurodegeneration in relation to immobility in the MPTP-treated common marmoset,a model for Parkinson’s disease [J].PLoS One,2012,7(10):e46371.
[30] Riverol M,Ordóňez C,Collantes M,et al.Levodopa induces long-lasting modification in the functional activity of the nigrostriatal pathway [J].Neurobiol Dis,2014,62(2):250-259.
[31] Peng S,Ma Y,Flores J,et al.Modulation of abnormal metabolic brain networks by experimental therapies in a nonhuman primate model of Parkinson disease:an application to human retinal pigment epithelial cell implantation [J].J Nucl Med,2016,57(10):1591-1598.
[32] Thomae D,Morley TJ,Lee HS,et al.Identification and in vivo evaluation of a fluorine-18 rolipram analogue,[18F]MNI-617,as a radioligand for PDE4 imaging in mammalian brain [J].J Labelled Comp Radiopharm,2016,59(5):205-213.
[33] Borghammer P,Cumming P,Aanerud J,et al.Subcortical elevation of metabolism in Parkinson’s disease-A critical reappraisal in the context of global mean normalization [J].Neuroimage,2009,47(4):1514-1521.
[34] Jenkins BG,Brouillet E,Chen YC,et al.Non-invasive neurochemical analysis of focal excitotoxic lesions in models of neurodegenerative illness using spectroscopic imaging [J].J Cereb Blood Flow Metab,1996,16(3):450-461.
[35] Guzman R,L?vblad KO,Meyer M,et al.Imaging the rat brain on a 1.5 T clinical MR-scanner [J].J Neurosci Methods,2000,97(1):77-85.
[36] Bjarkam CR,Nielsen MS,Glud AN,et al.Neuromodulation in a minipig MPTP model of Parkinson disease [J].Br J Neurosurg,2008,22(1):S9-12.
[37] Cumming P,Borghammer P.Molecular imaging and the neuropathologies of Parkinson’s disease [J].Curr Top Behav Neurosci,2012,11(10):117-148.
[38] Andringa G,Drukarch B,Bol JG,et al.Pinhole SPECT imaging of dopamine transporters correlates with dopamine transporter immunohistochemical analysis in the MPTP mouse model of Parkinson’s disease [J].Neuroimage,2005,26(4):1150-1158.
[39] Alvarez-Fischer D,Blessmann G,Trosowski C,et al.Quantitative [(123)I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels,but not number of nigral neurons in different mouse models of Parkinson’s disease [J].Neuroimage,2007,38(1):5-12.
[40] Niňerola-Baizán A,Rojas S,Bonastre M,et al.In vivo evaluation of the dopaminergic neurotransmission system using [123I]FP-CIT SPECT in 6-OHDA lesioned rats [J].Contrast Media Mol Imaging,2015,10(1):67-73.
[41] Sven R,Suwijn,Kora de Bruin,et al.The role of SPECT imaging of the dopaminergic system in translational research on Parkinson’s disease [J].Parkinsonism Relat Disord,2014,20(1):S184-S186.
[2] Sun Q,Wang T,Jiang TF,et al.Effect of a leucine-rich repeat kinase 2 variant on motor and non-motor symptoms in Chinese Parkinson’s disease patients [J].Aging Dis,2016,7(3):230-236.
[3] Wang G,Huang Y,Chen W,et al.Variants in the SNCA gene associate with motor progression while variants in the MAPT gene associate with the severity of Parkinson’s disease [J].Parkinsonism Relat Disord,2016,24(3):89-94.
[4] Wang W,Wang X,Fujioka H,et al.Parkinson’s disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes [J].Nat Med,2016,22(1):54-63.
[5] Yang X,Lou Y,Liu G,et al.Microglia P2Y6 receptor is related to Parkinson’s disease through neuroinflammatory process [J].J Neuroinflammation,2017,14(1):38.
[6] Jiang QW,Wang C,Zhou Y,et al.Plasma epidermal growth factor decreased in the early stage of Parkinson’s disease [J].Aging Dis,2015,6(3):168-173.
[7] Ma J,Jiang Q,Xu J,et al.Plasma insulin-like growth factor 1 is associated with cognitive impairment in Parkinson’s disease [J].Dement Geriatr Cogn Disord,2015,39(5-6):251-256.
[8] Kang WY,Yang Q,Jiang XF,et al.Salivary DJ-1 could be an indicator of Parkinson’s disease progression [J].Front Aging Neurosci,2014,6(6):102.
[9] Chen Y,Gao C,Sun Q,et al.MicroRNA-4639 is a regulator of DJ-1 expression and a potential early diagnostic marker for Parkinson’s disease [J].Front Aging Neurosci,2017,9(7):232.
[10] Halliday G,Lees A,Stern M.Milestones in Parkinson’s disease:clinical and pathologic features [J].Mov Disord,2011,26(6):1015-1021.
[11] 王琴,张春银.小动物PET在缺血性脑血管病中的应用进展[J].中国医学影像技术,2014,30(7):1117-1120.
[12] Oh-Ici D,Wespi P,Busch J,et al.Hyperpolarized metabolic MR imaging of acute myocardial changes and recovery after ischemia-reperfusion in a small-animal mode [J].Radiology,2016,278(3):742-751.
[13] Borghammer P.Perfusion and metabolism imaging studies in Parkinson’s disease [J].Dan Med J.2012,59(6):B4466.
[14] Kang W,Chen W,Yang Q,et al.Salivary total alpha-synuclein,oligomeric alpha-synuclein and SNCA variants in Parkinson’s disease patients [J].Sci Rep,2016,6(6):28143.
[15] 冯悦,钟萌,陈跃.小动物PET/CT显像考察麻黄碱干预棕色脂肪18F-FDG摄取的研究 [J].泸州医学院学报,2015,38(4):341-343.
[16] 凌泽民,唐颖,李颖勤,等.小动物PET-CT在大鼠臂丛根性撕脱脊髓损伤的应用研究 [J].解剖学研究,2015,37(2):88-92.
[17] Huang P,Tan YY,Liu DQ,et al.Motor-symptom laterality affects acquisition in Parkinson’s disease:a cognitive and functional magnetic resonance imaging study [J].Mov Disord,2017,32(7):1047-1055.
[18] Honer M,Hengerer B,Blagoev M,et al.Comparison of [18F]FDOPA,[18F]FMT and [18F]FECNT for imaging dopaminergic neurotransmission in mice [J].Nucl Med Biol,2006,33(5):607-614.
[19] Casteels C,Vermaelen P,Nuyts J,et al.Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain[J].J Nucl Med,2006,47(11):1858-1866.
[20] Casteels C,Lauwers E,Bormans G,et al.Metabolic-dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease[J].Eur J Nucl Med Mol Imaging,2008,35(1):124-134.
[21] Sun W,Sugiyama K,Fang X,et al.Different striatal D2-like receptor function in an early stage after unilateral striatal lesion and medial forebrain bundle lesion in rats[J].Brain Res,2010,1317(4):227-235.
[22] Jang DP,Min HK,Lee SY,et al.Functional neuroimaging of the 6-OHDA lesion rat model of Parkinson’s disease[J].Neurosci Lett,2012,513(2):187-192.
[23] D?br?ssy MD,Braun F,Klein S,et al.[18F]desmethoxyfallypride as a novel PET radiotracer for quantitative in vivo dopamine D2/D3 receptor imaging in rat models of neurodegenerative diseases[J].Nucl Med Biol,2012,39(7):1077-1080.
[24] Li X,Chen Z,Tang J,et al.Synthesis and biological evaluation of 10-11C-dihydrotetrabenazine as a vesicular monoamine transporter 2 radioligand [J].Arch Pharm (Weinheim),2014,347(5):313-319.
[25] Bu L,Li R,Liu H,et al.Intrastriatal transplantation of retinal pigment epithelial cells for the treatment of Parkinson disease:in vivo longitudinal molecular imaging with18F-P3BZA PET/CT [J].Radiology,2014,272(1):174-183.
[26] Park BN,Kim JH,Lee K,et al.Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson’s disease:small animal positron emission tomography study with18F-FP-CIT [J].Eur Radiol,2015,25(5):1487-1496.
[27] Zhou X,Doorduin J,Elsinga PH.et al.Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia [J].Neuroimage,2017,157(8):209-218.
[28] Crabbé M,Van der Perren A,Weerasekera A,et al.Altered mGluR5 binding potential and glutamine concentration in the 6-OHDA rat model of acute Parkinson’s disease and levodopa-induced dyskinesia [J].Neurobiol Aging,2018,61(1):82-92.
[29] Ando K,Obayashi S,Nagai Y,et al.PET analysis of dopaminergic neurodegeneration in relation to immobility in the MPTP-treated common marmoset,a model for Parkinson’s disease [J].PLoS One,2012,7(10):e46371.
[30] Riverol M,Ordóňez C,Collantes M,et al.Levodopa induces long-lasting modification in the functional activity of the nigrostriatal pathway [J].Neurobiol Dis,2014,62(2):250-259.
[31] Peng S,Ma Y,Flores J,et al.Modulation of abnormal metabolic brain networks by experimental therapies in a nonhuman primate model of Parkinson disease:an application to human retinal pigment epithelial cell implantation [J].J Nucl Med,2016,57(10):1591-1598.
[32] Thomae D,Morley TJ,Lee HS,et al.Identification and in vivo evaluation of a fluorine-18 rolipram analogue,[18F]MNI-617,as a radioligand for PDE4 imaging in mammalian brain [J].J Labelled Comp Radiopharm,2016,59(5):205-213.
[33] Borghammer P,Cumming P,Aanerud J,et al.Subcortical elevation of metabolism in Parkinson’s disease-A critical reappraisal in the context of global mean normalization [J].Neuroimage,2009,47(4):1514-1521.
[34] Jenkins BG,Brouillet E,Chen YC,et al.Non-invasive neurochemical analysis of focal excitotoxic lesions in models of neurodegenerative illness using spectroscopic imaging [J].J Cereb Blood Flow Metab,1996,16(3):450-461.
[35] Guzman R,L?vblad KO,Meyer M,et al.Imaging the rat brain on a 1.5 T clinical MR-scanner [J].J Neurosci Methods,2000,97(1):77-85.
[36] Bjarkam CR,Nielsen MS,Glud AN,et al.Neuromodulation in a minipig MPTP model of Parkinson disease [J].Br J Neurosurg,2008,22(1):S9-12.
[37] Cumming P,Borghammer P.Molecular imaging and the neuropathologies of Parkinson’s disease [J].Curr Top Behav Neurosci,2012,11(10):117-148.
[38] Andringa G,Drukarch B,Bol JG,et al.Pinhole SPECT imaging of dopamine transporters correlates with dopamine transporter immunohistochemical analysis in the MPTP mouse model of Parkinson’s disease [J].Neuroimage,2005,26(4):1150-1158.
[39] Alvarez-Fischer D,Blessmann G,Trosowski C,et al.Quantitative [(123)I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels,but not number of nigral neurons in different mouse models of Parkinson’s disease [J].Neuroimage,2007,38(1):5-12.
[40] Niňerola-Baizán A,Rojas S,Bonastre M,et al.In vivo evaluation of the dopaminergic neurotransmission system using [123I]FP-CIT SPECT in 6-OHDA lesioned rats [J].Contrast Media Mol Imaging,2015,10(1):67-73.
[41] Sven R,Suwijn,Kora de Bruin,et al.The role of SPECT imaging of the dopaminergic system in translational research on Parkinson’s disease [J].Parkinsonism Relat Disord,2014,20(1):S184-S186.