Michele Matarazzo, Alexandra Pérez-Soriano, Nasim Vafai, Elham Shahinfard, Kevin Ju-Chieh Cheng, Jessamyn McKenzie, Nicole Neilson, Qing Miao, Paul Schaffer, Hitoshi Shinotoh, Jeffrey H. Kordower, Vesna Sossi, A. Jon Stoessl
{"title":"帕金森病和帕金森病相关认知障碍中的错折叠蛋白沉积,一项[11C]PBB3 研究","authors":"Michele Matarazzo, Alexandra Pérez-Soriano, Nasim Vafai, Elham Shahinfard, Kevin Ju-Chieh Cheng, Jessamyn McKenzie, Nicole Neilson, Qing Miao, Paul Schaffer, Hitoshi Shinotoh, Jeffrey H. Kordower, Vesna Sossi, A. Jon Stoessl","doi":"10.1038/s41531-024-00708-z","DOIUrl":null,"url":null,"abstract":"<p>Parkinson’s disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [<sup>11</sup>C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson’s disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [<sup>11</sup>C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [<sup>11</sup>C](+)DTBZ to assess dopaminergic denervation and [<sup>11</sup>C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [<sup>11</sup>C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [<sup>11</sup>C]PBB3 and [<sup>11</sup>C]PBR28 binding in nigrostriatal regions. [<sup>11</sup>C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [<sup>11</sup>C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Misfolded protein deposits in Parkinson’s disease and Parkinson’s disease-related cognitive impairment, a [11C]PBB3 study\",\"authors\":\"Michele Matarazzo, Alexandra Pérez-Soriano, Nasim Vafai, Elham Shahinfard, Kevin Ju-Chieh Cheng, Jessamyn McKenzie, Nicole Neilson, Qing Miao, Paul Schaffer, Hitoshi Shinotoh, Jeffrey H. Kordower, Vesna Sossi, A. Jon Stoessl\",\"doi\":\"10.1038/s41531-024-00708-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Parkinson’s disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [<sup>11</sup>C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson’s disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [<sup>11</sup>C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [<sup>11</sup>C](+)DTBZ to assess dopaminergic denervation and [<sup>11</sup>C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [<sup>11</sup>C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [<sup>11</sup>C]PBB3 and [<sup>11</sup>C]PBR28 binding in nigrostriatal regions. [<sup>11</sup>C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [<sup>11</sup>C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.</p>\",\"PeriodicalId\":19706,\"journal\":{\"name\":\"NPJ Parkinson's Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2024-05-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Parkinson's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41531-024-00708-z\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Parkinson's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41531-024-00708-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
帕金森病(PD)与折叠错误的α-突触核蛋白和其他蛋白质(包括tau)的聚集有关。我们设计了一项横断面研究来量化[11C]PBB3(一种已知能与错误折叠的tau结合的配体,也可能与α-突触核蛋白结合)在帕金森病(PD)患者(有认知障碍或无认知障碍)和健康对照组(HC)中的脑结合情况,以此作为错误折叠蛋白聚集的替代物。在这项横断面研究中,19 名认知功能正常的帕金森病受试者(CN-PD)、13 名认知功能受损的帕金森病受试者(CI-PD)和 10 名健康对照者接受了 [11C]PBB3 PET 扫描。部分帕金森病受试者还接受了[11C](+)DTBZ PET成像以评估多巴胺能神经支配,以及[11C]PBR28 PET成像以评估神经炎症。与HC相比,PD受试者的后部丘脑显示出更高的[11C]PBB3结合率,而黑质则没有。不同受试者黑质区域的[11C]PBB3和[11C]PBR28结合率之间没有关系。与 CN-PD 和 HC 相比,CI-PD 前扣带回的[11C]PBB3 结合率升高,所有 PD 受试者的认知评分与该区域的[11C]PBB3 结合率呈反相关。我们的研究结果表明,在帕金森氏症中,蛋白质异常沉积主要集中在后部的普特明。这表明纹状体轴突末端优先参与了帕金森病的病理生理学。此外,我们的研究结果还表明,扣带回前部的病理变化可能是帕金森病认知功能障碍的重要体内标志,这与之前的神经病理学研究结果一致。
Misfolded protein deposits in Parkinson’s disease and Parkinson’s disease-related cognitive impairment, a [11C]PBB3 study
Parkinson’s disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [11C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson’s disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [11C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [11C](+)DTBZ to assess dopaminergic denervation and [11C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [11C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [11C]PBB3 and [11C]PBR28 binding in nigrostriatal regions. [11C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [11C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.
期刊介绍:
npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.