Milena Sales Pitombeira1,2, Michel Koole3, Kenia R Campanholo1,2, Aline M Souza2, Fábio L S Duran4, Davi J Fontoura Solla5, Maria F Mendes1, Samira L Apóstolos Pereira1, Carolina M Rimkus6, Geraldo Filho Busatto4, Dagoberto Callegaro1, Carlos A Buchpiguel2, Daniele de Paula Faria7. 1. Department of Neurology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. 2. Laboratory of Nuclear Medicine (LIM43), Department of Radiology and Oncology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. 3. Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, KU Leuven, Flanders, Belgium. 4. Laboratory of Psychiatric Neuroimaging (LIM21), Department of Psychiatry, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. 5. Department of Neurology, Division of Neurosurgery, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. 6. Department of Radiology and Oncology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. 7. Laboratory of Nuclear Medicine (LIM43), Department of Radiology and Oncology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. danielefaria1@gmail.com.
Abstract
PURPOSE: Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity. METHODS: We used the 18-kDa translocator protein (TSPO) tracer (R)-[11C]PK11195 and [11C]PIB PET images acquired in a hybrid PET/MR 3 T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT). RESULTS: In the VOI-based analysis, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). CONCLUSIONS: Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.
PURPOSE: Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity. METHODS: We used the 18-kDa translocator protein (TSPO) tracer (R)-[11C]PK11195 and [11C]PIB PET images acquired in a hybrid PET/MR 3 T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT). RESULTS: In the VOI-based analysis, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). CONCLUSIONS: Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.
Authors: Alexandra Kutzelnigg; Claudia F Lucchinetti; Christine Stadelmann; Wolfgang Brück; Helmut Rauschka; Markus Bergmann; Manfred Schmidbauer; Joseph E Parisi; Hans Lassmann Journal: Brain Date: 2005-10-17 Impact factor: 13.501
Authors: Yao Lulu Xing; Philipp T Röth; Jo Anne S Stratton; Bernard H A Chuang; Jill Danne; Sarah L Ellis; Sze Woei Ng; Trevor J Kilpatrick; Tobias D Merson Journal: J Neurosci Date: 2014-10-15 Impact factor: 6.167
Authors: Katharina Heß; Laura Starost; Nicholas W Kieran; Christian Thomas; Maria C J Vincenten; Jack Antel; Gianvito Martino; Inge Huitinga; Luke Healy; Tanja Kuhlmann Journal: Acta Neuropathol Date: 2020-07-24 Impact factor: 17.088
Authors: Ryo Yamasaki; Haiyan Lu; Oleg Butovsky; Nobuhiko Ohno; Anna M Rietsch; Ron Cialic; Pauline M Wu; Camille E Doykan; Jessica Lin; Anne C Cotleur; Grahame Kidd; Musab M Zorlu; Nathan Sun; Weiwei Hu; LiPing Liu; Jar-Chi Lee; Sarah E Taylor; Lindsey Uehlein; Debra Dixon; Jinyu Gu; Crina M Floruta; Min Zhu; Israel F Charo; Howard L Weiner; Richard M Ransohoff Journal: J Exp Med Date: 2014-07-07 Impact factor: 14.307
Authors: Maria L Elkjaer; Tobias Frisch; Richard Reynolds; Tim Kacprowski; Mark Burton; Torben A Kruse; Mads Thomassen; Jan Baumbach; Zsolt Illes Journal: Acta Neuropathol Commun Date: 2019-12-11 Impact factor: 7.801