Tau-PET Bildgebung der Demenzerkrankungen

Zusammenfassung

Die Ablagerung von Tau-Proteinen ist ein grundlegendes pathophysiologisches Merkmal vieler neurodegenerativer Demenzerkrankungen. Die Entwicklung sensitiver Tau-PET Tracer in den letzten Jahren hat die Lokalisation von Tau-Ablagerungen in unterschiedlichen klinischen neurodegenerativen Phänotypen in vivo ermöglicht. Bei der Alzheimer Demenz sind die räumlichen Muster der Tau-Pathologie in temporalen, parietalen und frontalen Regionen mit der Neurodegeneration und klinischen Symptomatik korreliert. Des Weiteren zeigen sich Zusammenhänge mit der Schwere der kognitiven Beeinträchtigung und der gemessenen Tau-Last, sodass Tau-PET in Zukunft einen hohen Nutzen in der klinischen Anwendung zugesprochen werden könnte. Bei primären Tauopathien, neurodegenerative Erkrankungen wie z.B. PSP und CBD, deren dominantes pathophysiologisches Merkmal die Ansammlung von Tau-Proteinen im Gehirn sind, steht die Validierung der wissenschaftlich genutzten Tau-PET Tracer noch aus, aber erste Hinweise aus Studien mit Tau-PET Tracern der zweiten Generation sind vielversprechend. Diese zeigen, dass die räumliche Verteilung der Tracer-Anreicherung bei primären Tauopathien von dem räumlichen Verteilungsmuster bei der Alzheimer Demenz unterschieden werden kann.

Dennoch fehlen aktuell wichtige Validierungsstudien, die in größeren Kohorten den direkten klinischen Nutzen der Tau-PET Bildgebung belegen. Auf der anderen Seite haben die bisherigen wissenschaftlichen Erkenntnisse, die durch die Tau-PET Bildgebung gewonnen wurden, bereits einen wesentlichen Beitrag zum Zusammenhang von Tau-Pathologie und Neurodegeneration geleistet.

Abstract

Tauopathies are a fundamental pathophysiological feature of many neurodegenerative disorders. The development of sensitive tau-PET tracers in recent years has enabled the study of pathophysiological tau deposition in different clinical neurodegenerative phenotypes. In Alzheimer’s dementia (AD), patterns of tau pathology in temporal, parietal, and frontal regions are associated with measures of neurodegeneration and clinical symptomatology. Furthermore, correlations with the severity of cognitive impairment in AD patients and the measured tau load could be established, underscoring the potential utility of tau-PET Imaging in the clinical routine. For primary tauopathies, validation of the currently available tau-PET tracers is still pending, but initial indications from studies with second-generation tau-PET tracers seem promising. Accumulative initial evidence shows that the spatial distribution of tracer activity in primary tauopathies (i.e., PSP or CBD) can be distinguished from the spatial distribution pattern of in vivo tau-PET in AD. Nevertheless, important validation studies demonstrating the direct clinical utility of tau-PET imaging in larger cohorts are currently lacking. On the other hand, the scientific knowledge gained by tau-PET imaging has made a significant contribution to our understanding of the relationship between tau pathology and neurodegeneration.

Schlüsselwörter

Tauopathien - Alzheimer Demenz - Tau-PET Tracer - Bildgebung

Keywords

Tauopathies - Alzheimer’s Disease - tau PET tracers - imaging

Publication History

Article published online:
02 December 2022

• Literatur

• 1 Goedert M, Eisenberg DS, Crowther RA. Propagation of Tau Aggregates and Neurodegeneration. Annu Rev Neurosci 2017; 40: 189-210
• 2 Bischof GN, Endepols H, van Eimeren T. et al. Tau-imaging in neurodegeneration. Methods 2017; 130: 114-123
• 3 Ossenkoppele R, Rabinovici GD, Smith R. et al. Discriminative Accuracy of [18F]flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA 2018; 320: 1151-1162
• 4 Leuzy A, Smith R, Ossenkoppele R. et al. Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders. JAMA Neurol 2020;
• 5 Mintun MA, Lo AC, Duggan Evans C. et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med 2021; 384: 1691-1704
• 6 Okamura N, Harada R, Ishiki A. et al. The development and validation of tau PET tracers: current status and future directions. Clin Transl Imaging 2018; 6: 305-316
• 7 Hostetler ED, Walji AM, Zeng Z. et al. Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles. Journal of Nuclear Medicine 2016; 57: 1599-1606
• 8 Mueller A, Bullich S, Barret O. et al. Tau PET imaging with 18F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study. J Nucl Med 2020; 61: 911-919
• 9 Wong DF, Comley RA, Kuwabara H. et al. Characterization of 3 Novel Tau Radiopharmaceuticals, 11C-RO-963, 11C-RO-643, and 18F-RO-948, in Healthy Controls and in Alzheimer Subjects. J Nucl Med 2018; 59: 1869-1876
• 10 Declercq LD, Rombouts F, Koole M. et al. Preclinical Evaluation of (18)F-JNJ64349311, a Novel PET Tracer for Tau Imaging . J Nucl Med 2017; 58: 975-981
• 11 Sanabria Bohórquez S, Marik J, Ogasawara A. et al. [18F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2019; 46: 2077-2089
• 12 Ng KP, Pascoal TA, Mathotaarachchi S. et al. Monoamine oxidase B inhibitor, selegiline, reduces (18)F-THK5351 uptake in the human brain. Alzheimers Res Ther 2017; 9: 25
• 13 Villemagne V, Dore V, Okamura N. et al. To tau or to MAO-B? Most of the 18F-THK5351 signal is blocked by selegiline. J Nucl Med 2018; 59: 1644-1644
• 14 Leuzy A, Chiotis K, Lemoine L. et al. Tau PET imaging in neurodegenerative tauopathies-still a challenge . Mol Psychiatry 2019; 24: 1112-1134
• 15 Bischof GN, Dodich A, Boccardi M. et al. Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Eur J Nucl Med Mol Imaging 2021; 48: 2110-2120
• 16 Fleisher AS, Pontecorvo MJ, Devous MD. et al. Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes. JAMA Neurol 2020; 77: 829-839
• 17 Eli Lilly and Company. Lilly Receives U.S. FDA Approval of TAUVIDTM (flortaucipir F 18 injection) for Use in Patients Being Evaluated for Alzheimer’s Disease. Accessed May 28, 2022 at: https://investor.lilly.com/news-releases/news-release-details/lilly-receives-us-fda-approval-tauvidtm-flortaucipir-f-18
• 18 Morris E, Chalkidou A, Hammers A. et al. Diagnostic accuracy of 18F amyloid PET tracers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 2016; 43: 374-385
• 19 Clark CM, Schneider JA, Bedell BJ. et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305: 275-283
• 20 Sabri O, Sabbagh MN, Seibyl J. et al. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: Phase 3 study. Alzheimer‘s & Dementia 2015; 11: 964-974
• 21 Beach TG, Thal DR, Zanette M. et al. Detection of Striatal Amyloid Plaques with [18F]flutemetamol: Validation with Postmortem Histopathology. J Alzheimers Dis 2016; 52: 863-873
• 22 Jack CR, Wiste HJ, Botha H. et al. The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes. Brain 2019; 142: 3230-3242
• 23 Ossenkoppele R, Binette AP, Groot C. et al. Amyloid and Tau PET positive cognitively unimpaired individuals: Destined to decline?. medRxiv
• 24 Crary JF, Trojanowski JQ, Schneider JA. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 2014; 128: 755-766
• 25 Duyckaerts C, Braak H, Brion J-P. et al. PART is part of Alzheimer disease. Acta Neuropathol 2015; 129: 749-756
• 26 Krishnadas N, Doré V, Groot C. et al. Mesial temporal tau in amyloid-β-negative cognitively normal older persons. Alzheimers Res Ther 2022; 14: 51
• 27 Johnson KA, Schultz A, Betensky RA. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Annals of neurology 2016; 79: 110-9
• 28 Schöll M, Lockhart SN, Schonhaut DR. et al. PET Imaging of Tau Deposition in the Aging Human Brain. Neuron 2016; 89: 971-982
• 29 Jack CR, Wiste HJ, Schwarz CG. et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain 2018; 141: 1517-1528
• 30 Harrison TM, La Joie R, Maass A. et al. Longitudinal tau accumulation and atrophy in aging and alzheimer disease. Ann Neurol 2019; 85: 229-240
• 31 Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiology of aging 1995; 16: 271-278
• 32 Schöll M, Ossenkoppele R, Strandberg O. et al. Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease. Brain 2017; 140: 2286-2294
• 33 Burnham SC, Bourgeat P, Doré V. et al. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer’s disease pathophysiology (SNAP) or Alzheimer’s disease pathology: a longitudinal study. Lancet Neurol 2016; 15: 1044-1053
• 34 Boccardi M, Dodich A, Albanese E. et al. The strategic biomarker roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update. Eur J Nucl Med Mol Imaging 2021; 48: 2070-2085
• 35 Wolters EE, Dodich A, Boccardi M. et al. Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase biomarker development framework. Eur J Nucl Med Mol Imaging 2021; 48: 2097-2109
• 36 Bischof GN, Jessen F, Fliessbach K. et al. Impact of tau and amyloid burden on glucose metabolism in Alzheimer’s disease. Ann Clin Transl Neurol 2016; 3: 934-939
• 37 Hall B, Mak E, Cervenka S. et al. In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings. Ageing Research Reviews 2017; 36: 50-63
• 38 Hashimoto H, Kawamura K, Igarashi N. et al. Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology. Journal of Nuclear Medicine 2014; 55: 1532-1538
• 39 Josephs KA, Whitwell JL, Tacik P. et al. [18F]AV-1451 tau-PET uptake does correlate with quantitatively measured 4R-tau burden in autopsy-confirmed corticobasal degeneration. Acta Neuropathologica 2016; 132: 931-933
• 40 Stepanov V, Svedberg M, Jia Z. et al. Development of [11C]/[3H]THK-5351 - A potential novel carbon-11 tau imaging PET radioligand. Nuclear Medicine and Biology 2017; 46: 50-53
• 41 Tago T, Furumoto S, Okamura N. et al. Structure-Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease. Journal of Nuclear Medicine 2016; 57: 608-614
• 42 Dronse J, Fliessbach K, Bischof GN. et al. In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer’s Disease. J Alzheimers Dis 2016; 55: 465-471
• 43 Hammes J, Bischof GN, Giehl K. et al. Elevated in vivo [18F]-AV-1451 uptake in a patient with progressive supranuclear palsy . Mov Disord 2016; 32: 170-171
• 44 Schonhaut DR, McMillan CT, Spina S. et al. 18 F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study. Ann Neurol 2017; 82: 622-634
• 45 Marquié M, Normandin MD, Vanderburg CR. et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 2015; 78: 787-800
• 46 Marquié M, Verwer EE, Meltzer AC. et al. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case. Acta Neuropathol Commun 2017; 5: 75
• 47 Willroider M, Roeber S, Horn AKE. et al. Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [18F]PI-2620. Front Neurol 2021; 12: 684523
• 48 Brendel M, Barthel H, Eimeren T van. et al. Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy . JAMA Neurol 2020; 77: 1-13
• 49 Li L, Liu F-T, Li M. et al. Clinical Utility of 18 F-APN-1607 Tau PET Imaging in Patients with Progressive Supranuclear Palsy. Mov Disord 2021; 36: 2314-2323
• 50 Hammes J, Bischof GN, Bohn KP. et al. One stop shop: Flortaucipir PET differentiates amyloid positive and negative forms of neurodegenerative diseases . J Nucl Med 2021; 62: 240-246
• 51 Hammes J, Leuwer I, Bischof GN. et al. Multimodal correlation of dynamic [18F]-AV-1451 perfusion PET and neuronal hypometabolism in [18F]-FDG PET. Eur J Nucl Med Mol Imaging 2017; 44: 2249-2256
• 52 Jack CR, Bennett DA, Blennow K. et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 2016; 87: 539-547
• 53 Wren MC, Lashley T, Årstad E. et al. Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias. Acta Neuropathologica Communications 2018; 6: 34
• 54 Iseki E, Togo T, Suzuki K. et al. Dementia with Lewy bodies from the perspective of tauopathy. Acta Neuropathologica 2003; 105: 265-270
• 55 Schmidt ML, Martin JA, Lee VM. et al. Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer’s disease and Lewy body disorders. Acta Neuropathol 1996; 91: 475-481