Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With β-Amyloid–Negative CBS
Abstract
Background and Objectives
Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)–negative CBS.
Methods
We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction).
Results
Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = −0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model.
Discussion
[18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.
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© 2023 American Academy of Neurology.
Publication History
Received: March 24, 2023
Accepted: October 3, 2023
Published online: December 14, 2023
Published in print: January 9, 2024
Disclosure
C. Palleis is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. N. Franzmeier served as a consultant for MSD, has received speaker honoraria from LMI and has funded research collaborations with Avid Radiopharmaceuticals. E. Weidinger reports no disclosures relevant to the manuscript. A. Bernhardt reports no disclosures relevant to the manuscript. S. Katzdobler reports no disclosures relevant to the manuscript. S. Wall reports no disclosures relevant to the manuscript. C. Ferschmann reports no disclosures relevant to the manuscript. S. Harris reports no disclosures relevant to the manuscript. J. Schmitt reports no disclosures relevant to the manuscript. S. Schuster reports no disclosures relevant to the manuscript. J. Gnörich reports no disclosures relevant to the manuscript. A. Finze reports no disclosures relevant to the manuscript. G. Biechele reports no disclosures relevant to the manuscript. S. Lindner reports no disclosures relevant to the manuscript. N. L. Albert reports no disclosures relevant to the manuscript. P. Bartenstein reports no disclosures relevant to the manuscript. O. Sabri received research support from Life Molecular Imaging. H. Barthel received reader honoraria from Life Molecular Imaging and speaker honoraria from Novartis/AAA. R. Rupprecht is on the advisory board for Biogen, and has consulted for GABA Therapeutics. B. Nuscher reports no disclosures relevant to the manuscript. A.W. Stephens is employee of Life Molecular Imaging. B.-S. Rauchmann reports no disclosures relevant to the manuscript. R. Perneczky is on the advisory board for Biogen and has consulted for Eli Lilly, he is a grant recipient from Janssen Pharmaceutica and Boehringer Ingelheim, and has received speaker honoraria from Janssen-Cilag, Pfizer and Biogen. C. Haass collaborates with DENALI therapeutics. M. Brendel received speaker honoraria from GE healthcare and Life Molecular Imaging and is an advisor of Life Molecular Imaging. J. Levin reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers. J. Levin is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. G.U. Höglinger serves as a consultant for Abbvie, Alzprotect, Aprineua, Asceneuron, Bial, Biogen, Biohaven, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, UCB; received honoraria for scientific presentations from Abbvie, Bayer Vital, Bial, Biogen, Bristol Myers Squibb, Kyowa Kirin, Roche, Teva, UCB, Zambon; and holds a patent on Treatment of Synucleinopathies (US 10,918,628 B2; EP 3 525 788). Go to Neurology.org/N for full disclosures.
Study Funding
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) to P. Bartenstein, R. Rupprecht and N.L. Albert (project numbers 421887978, 422182557), and to M. Brendel (project numbers BR4580/1-1/RO5194/1-1). The recruitment of the ActiGliA cohort was supported by the presidential fond of the Helmholtz society (to C. Haass). This project was also supported by the German Center for Neurodegenerative Diseases (DZNE, DescribePSP Study), the German Parkinson's Association (DPG, ProPSP Study) and the Hirnliga e.V. (Manfred-Strohscheer-Stiftung). Tau-PET imaging was funded by the Alzheimer Forschung Initiative e.V. (grant number #19063p). C. Palleis, P. Bartenstein, G.U. Höglinger, C. Haass, J. Levin, M. Brendel and R. Perneczky were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy: ID 390857198). G.U. Höglinger and C. Haass were also funded by the NOMIS foundation (FTLD project), Volkswagen Stiftung/Lower Saxony Ministry for Science/Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies), European Joint Programme on Rare Diseases (Improve-PSP). The Lüneburg Heritage has supported the work of C. Palleis, S. Katzdobler and J. Levin. The Friedrich-Baur-Stiftung has supported the work of C. Palleis.
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