18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy
Abstract Background Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18F...
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2025-02-01
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| author | Michael L. Alosco Jhony Mejía Pérez Julia E. Culhane Ranjani Shankar Christopher J. Nowinski Samantha Bureau Nidhi Mundada Karen Smith Alinda Amuiri Breton Asken Jenna R. Groh Annalise Miner Erika Pettway Sydney Mosaheb Yorghos Tripodis Charles Windon Gustavo Mercier Robert A. Stern Lea T. Grinberg David N. Soleimani-Meigooni Bradley T. Christian Tobey J. Betthauser Thor D. Stein Ann C. McKee Chester A. Mathis Eric E. Abrahamson Milos D. Ikonomovic Sterling C. Johnson Jesse Mez Renaud La Joie Daniel Schonhaut Gil D. Rabinovici |
| author_facet | Michael L. Alosco Jhony Mejía Pérez Julia E. Culhane Ranjani Shankar Christopher J. Nowinski Samantha Bureau Nidhi Mundada Karen Smith Alinda Amuiri Breton Asken Jenna R. Groh Annalise Miner Erika Pettway Sydney Mosaheb Yorghos Tripodis Charles Windon Gustavo Mercier Robert A. Stern Lea T. Grinberg David N. Soleimani-Meigooni Bradley T. Christian Tobey J. Betthauser Thor D. Stein Ann C. McKee Chester A. Mathis Eric E. Abrahamson Milos D. Ikonomovic Sterling C. Johnson Jesse Mez Renaud La Joie Daniel Schonhaut Gil D. Rabinovici |
| author_sort | Michael L. Alosco |
| collection | DOAJ |
| description | Abstract Background Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18F-MK-6240 tau PET study in former American football players. Methods Autoradiography and in-vitro binding studies were done using 3H-MK-6240 on frozen temporal and frontal cortex tissue from six autopsy cases with stage III CTE compared to Alzheimer’s disease. Thirty male former National Football League (NFL) players with cognitive concerns (mean age = 58.9, SD = 7.8) completed tau (18F-MK-6240) and Aβ (18F-Florbetapir) PET. Controls included 39 Aβ-PET negative, cognitively normal males (mean age = 65.7, SD = 6.3). 18F-MK-6240 SUVr images were created using 70–90 min post-injection data with inferior cerebellar gray matter as the reference. We compared SUVr between players and controls using voxelwise and region-of-interest approaches. Correlations between 18F-MK-6240 SUVr and cognitive scores were tested. Results All six CTE stage III cases had Braak NFT stage III but no neuritic plaques. Two had Thal Phase 1 for Aβ; one showed a laminar pattern of 3H-MK-6240 autoradiography binding in the superior temporal cortex and less so in the dorsolateral frontal cortex, corresponding to tau-immunoreactive lesions detected using the AT8 antibody (pSer202/pThr205 tau) in adjacent tissue sections. The other CTE cases had low frequencies of cortical tau-immunoreactive deposits and no well-defined autoradiography binding. In-vitro 3H-MK-6240 binding studies to CTE brain homogenates in the case with autoradiography signal indicated high binding affinity (KD = 2.0 ± 0.9 nM, Bmax = 97 ± 24 nM, n = 3). All NFL players had negative Aβ-PET. There was variable, low-to-intermediate intensity 18F-MK-6240 uptake across participants: 16 had no cortical signal, 7 had medial temporal lobe (MTL) uptake, 2 had frontal uptake, and 4 had MTL and frontal uptake. NFL players had higher SUVr in the entorhinal cortex (d = 0.86, p = 0.001), and the parahippocampal gyrus (d = 0.39, p = 0.08). Voxelwise regressions showed increased uptake in NFL players in two bilateral anterior MTL clusters (p < 0.05 FWE). Higher parahippocampal and frontal–temporal SUVrs correlated with worse memory (r = -0.38, r = -0.40) and semantic fluency (r = -0.38, r = -0.48), respectively. Conclusion We present evidence of 3H-MK-6240 in-vitro binding to post-mortem CTE tissue homogenates and in vivo 18F-MK-6240 PET binding in the MTL among a subset of participants. Additional studies in larger samples and PET-to-autopsy correlations are required to further elucidate the potential of 18F-MK-6240 to detect tau pathology in CTE. |
| format | Article |
| id | doaj-art-a661bb9efba04976bec858a99dcc85ac |
| institution | DOAJ |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Molecular Neurodegeneration |
| spelling | doaj-art-a661bb9efba04976bec858a99dcc85ac2025-08-20T03:03:23ZengBMCMolecular Neurodegeneration1750-13262025-02-0120111910.1186/s13024-025-00808-118F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathyMichael L. Alosco0Jhony Mejía Pérez1Julia E. Culhane2Ranjani Shankar3Christopher J. Nowinski4Samantha Bureau5Nidhi Mundada6Karen Smith7Alinda Amuiri8Breton Asken9Jenna R. Groh10Annalise Miner11Erika Pettway12Sydney Mosaheb13Yorghos Tripodis14Charles Windon15Gustavo Mercier16Robert A. Stern17Lea T. Grinberg18David N. Soleimani-Meigooni19Bradley T. Christian20Tobey J. Betthauser21Thor D. Stein22Ann C. McKee23Chester A. Mathis24Eric E. Abrahamson25Milos D. Ikonomovic26Sterling C. Johnson27Jesse Mez28Renaud La Joie29Daniel Schonhaut30Gil D. Rabinovici31Department of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoConcussion Legacy FoundationConcussion Legacy FoundationDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Clinical & Health Psychology, 1Florida Alzheimer’s Disease Research Center, Fixel Institute for Neurological Diseases, University of FloridaDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Biostatistics, Boston University School of Public HealthDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoMolecular Imaging and Nuclear Medicine, Boston Medical CenterDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoWisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-MadisonWisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Radiology, University of Pittsburgh School of MedicineDepartment of Neurology, University of Pittsburgh School of MedicineDepartment of Neurology, University of Pittsburgh School of MedicineWisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-MadisonDepartment of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Boston University, Chobanian & Avedisian School of MedicineDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoDepartment of Neurology, Alzheimer’s Disease Research Center, Memory & Aging Center, University of California San FranciscoAbstract Background Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18F-MK-6240 tau PET study in former American football players. Methods Autoradiography and in-vitro binding studies were done using 3H-MK-6240 on frozen temporal and frontal cortex tissue from six autopsy cases with stage III CTE compared to Alzheimer’s disease. Thirty male former National Football League (NFL) players with cognitive concerns (mean age = 58.9, SD = 7.8) completed tau (18F-MK-6240) and Aβ (18F-Florbetapir) PET. Controls included 39 Aβ-PET negative, cognitively normal males (mean age = 65.7, SD = 6.3). 18F-MK-6240 SUVr images were created using 70–90 min post-injection data with inferior cerebellar gray matter as the reference. We compared SUVr between players and controls using voxelwise and region-of-interest approaches. Correlations between 18F-MK-6240 SUVr and cognitive scores were tested. Results All six CTE stage III cases had Braak NFT stage III but no neuritic plaques. Two had Thal Phase 1 for Aβ; one showed a laminar pattern of 3H-MK-6240 autoradiography binding in the superior temporal cortex and less so in the dorsolateral frontal cortex, corresponding to tau-immunoreactive lesions detected using the AT8 antibody (pSer202/pThr205 tau) in adjacent tissue sections. The other CTE cases had low frequencies of cortical tau-immunoreactive deposits and no well-defined autoradiography binding. In-vitro 3H-MK-6240 binding studies to CTE brain homogenates in the case with autoradiography signal indicated high binding affinity (KD = 2.0 ± 0.9 nM, Bmax = 97 ± 24 nM, n = 3). All NFL players had negative Aβ-PET. There was variable, low-to-intermediate intensity 18F-MK-6240 uptake across participants: 16 had no cortical signal, 7 had medial temporal lobe (MTL) uptake, 2 had frontal uptake, and 4 had MTL and frontal uptake. NFL players had higher SUVr in the entorhinal cortex (d = 0.86, p = 0.001), and the parahippocampal gyrus (d = 0.39, p = 0.08). Voxelwise regressions showed increased uptake in NFL players in two bilateral anterior MTL clusters (p < 0.05 FWE). Higher parahippocampal and frontal–temporal SUVrs correlated with worse memory (r = -0.38, r = -0.40) and semantic fluency (r = -0.38, r = -0.48), respectively. Conclusion We present evidence of 3H-MK-6240 in-vitro binding to post-mortem CTE tissue homogenates and in vivo 18F-MK-6240 PET binding in the MTL among a subset of participants. Additional studies in larger samples and PET-to-autopsy correlations are required to further elucidate the potential of 18F-MK-6240 to detect tau pathology in CTE.https://doi.org/10.1186/s13024-025-00808-1Alzheimer’s diseaseBiomarkersChronic traumatic encephalopathyMK-6240Repetitive head impactsTau PET |
| spellingShingle | Michael L. Alosco Jhony Mejía Pérez Julia E. Culhane Ranjani Shankar Christopher J. Nowinski Samantha Bureau Nidhi Mundada Karen Smith Alinda Amuiri Breton Asken Jenna R. Groh Annalise Miner Erika Pettway Sydney Mosaheb Yorghos Tripodis Charles Windon Gustavo Mercier Robert A. Stern Lea T. Grinberg David N. Soleimani-Meigooni Bradley T. Christian Tobey J. Betthauser Thor D. Stein Ann C. McKee Chester A. Mathis Eric E. Abrahamson Milos D. Ikonomovic Sterling C. Johnson Jesse Mez Renaud La Joie Daniel Schonhaut Gil D. Rabinovici 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy Molecular Neurodegeneration Alzheimer’s disease Biomarkers Chronic traumatic encephalopathy MK-6240 Repetitive head impacts Tau PET |
| title | 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy |
| title_full | 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy |
| title_fullStr | 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy |
| title_full_unstemmed | 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy |
| title_short | 18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy |
| title_sort | 18f mk 6240 tau pet in patients at risk for chronic traumatic encephalopathy |
| topic | Alzheimer’s disease Biomarkers Chronic traumatic encephalopathy MK-6240 Repetitive head impacts Tau PET |
| url | https://doi.org/10.1186/s13024-025-00808-1 |
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