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Multicenter Study
. 2020 Nov 1;77(11):1408-1419.
doi: 10.1001/jamaneurol.2020.2526.

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy

Matthias Brendel  1 , Henryk Barthel  2 , Thilo van Eimeren  3   4   5 , Ken Marek  6   7 , Leonie Beyer  1 , Mengmeng Song  1 , Carla Palleis  8 , Mona Gehmeyr  8 , Urban Fietzek  8 , Gesine Respondek  9 , Julia Sauerbeck  1 , Alexander Nitschmann  1 , Christian Zach  1 , Jochen Hammes  3 , Michael T Barbe  4 , Oezguer Onur  4 , Frank Jessen  5   10   11 , Dorothee Saur  12 , Matthias L Schroeter  13   14   15 , Jost-Julian Rumpf  12 , Michael Rullmann  2 , Andreas Schildan  2 , Marianne Patt  2 , Bernd Neumaier  3   16 , Olivier Barret  6   7 , Jennifer Madonia  6   7 , David S Russell  6   7 , Andrew Stephens  17 , Sigrun Roeber  18 , Jochen Herms  18   19 , Kai Bötzel  8 , Joseph Classen  12 , Peter Bartenstein  1   20 , Victor Villemagne  21   22 , Johannes Levin  8   19 , Günter U Höglinger  9   19   20   23 , Alexander Drzezga  3   5   16 , John Seibyl  6   7 , Osama Sabri  2
Affiliations
Multicenter Study

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy

Matthias Brendel et al. JAMA Neurol. .

Erratum in

  • Error in Figure.
    [No authors listed] [No authors listed] JAMA Neurol. 2020 Nov 1;77(11):1453. doi: 10.1001/jamaneurol.2020.3037. JAMA Neurol. 2020. PMID: 32804190 Free PMC article. No abstract available.

Abstract

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.

Design, setting, and participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.

Main outcomes and measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.

Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.

Conclusions and relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Brendel reported personal fees from Life Molecular Imaging and personal fees from GE Healthcare outside the submitted work. Dr van Eimeren reported personal fees from Lundbeck and Eli Lilly outside the submitted work; Life Molecular Imaging provided the precursor for PI-2620 free of charge as part of a research collaboration agreement. Dr Marek reported other support from GE Healthcare, Life Molecular Imaging, Roche, Takeda, Lundbeck, NeuroDerm, UCB, Denali, and InviCRO outside the submitted work. Dr Fietzek reported personal fees from Ipsen and Allergan outside the submitted work. Dr Respondek reported serving on the advisory boards for UCB and Biogen. Dr Barbe reported grants from Medtronic and Boston Scientific and personal fees from Medtronic, St Jude, UCB, Bial, GE Healthcare, and Institute for Quality and Efficiency in Health Care outside the submitted work. Dr Jessen reported personal fees from Eisai, Biogen, GE Healthcare, Roche, and AC Immune outside the submitted work. Dr Patt reported grants from Life Molecular Imaging during the conduct of the study. Dr Barret reported other support from Piramal during the conduct of the study. Dr Russell reported other from InviCRO during the conduct of the study. Dr Stephens reported personal fees from Life Molecular Imaging outside the submitted work. Dr Villemagne reported grants from Piramal Imaging during the conduct of the study and personal fees from Shanghai Green Valley outside the submitted work. Dr Levin reported nonfinancial support from AbbVie and personal fees from MODAG GmbH, Axon Neuroscience, Bayer, Thieme Medical Publishers, and Kohlhammer GmbH Medical Publishers outside the submitted work. Dr Höglinger reported personal fees from AbbVie, Asceneuron, Biogen, Biohaven, Lundbeck, Novartis, Roche, Sanofi, and UCB outside the submitted work. Dr Drzezga reported nonfinancial support from Life Molecular Imaging during the conduct of the study; grants and personal fees from Siemens Healthineers, personal fees and nonfinancial support from Avid/Eli Lilly, and personal fees and nonfinancial support from GE Healthcare outside the submitted work. Dr Seibyl reported other support from InviCRO and Life Molecular Imaging during the conduct of the study and other support from Roche and Biogen outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. In Vitro Evaluation of 18F-PI-2620 Binding in Postmortem Tissue
A, The top row depicts AT8 immunohistochemistry together with autoradiograms of basal ganglia slices of a man in his late 60s with a postmortem diagnosis of progressive supranuclear palsy with Richardson syndrome (PSP-RS) after incubation with 18F-PI-2620 alone or with 18F-PI-2620 and excessive cold compound (19F-PI-2620) as well as autoradiograms of basal ganglia slices of a healthy female control in her early 60s. The lower row depicts AT8 immunohistochemistry together with autoradiograms of frontal cortex slices of a woman in her late 60s with a postmortem diagnosis of PSP-RS after incubation with 18F-PI-2620 or 18F-PI-2620 and excessive cold compound (19F-PI-2620) as well as autoradiograms of frontal cortex slices of a healthy male control in his late 30s. B, Quantification of ARG binding by region of interest analysis (basal ganglia: target-to-capsula-externa [CE] ratios; frontal cortex: target-to-white matter [WM] ratios). Four or 5 brain slices of each PSP-RS and healthy control (HC) sample were analyzed and the resulting data were compared by a t test. Confirmatory samples are shown in eFigure 3 in the Supplement. Patient details are provided in the eMethods in the Supplement.
Figure 2.
Figure 2.. 18F-PI-2620 Binding in Predefined PSP Target Regions
A, Average 18F-PI-2620 distribution volume ratio (DVR) binding maps presented as axial overlays on a standard magnetic resonance imaging template for all study groups. Extracerebral voxels were masked. B, 18F-PI-2620 DVR comparison between different study groups for the 9 evaluated progressive supranuclear palsy (PSP) target regions. Statistics derive from multivariate analysis of variance including center, age, and sex as covariates and Bonferroni adjustment for multiple comparisons. Error bars indicate mean (SD). α-syn indicates probable α-synucleinopathies; AD, Alzheimer disease; DC, controls with disease; HC, healthy controls; RS, Richardson syndrome. aP < .050. bP < .001. cP < .010.
Figure 3.
Figure 3.. Association of 18F-PI-2620 Binding With Age, Disease Severity, Disease Duration, and Phenotype
18F-PI-2620 binding as a function of age (A), disease severity (B), and disease duration (C), expressed as correlation plots. Additional plots are in eFigure 9 in the Supplement. rS indicates Spearman coefficients of correlations. Average 18F-PI-2620 distribution volume ratio (DVR) maps of different progressive supranuclear palsy (PSP) phenotypes illustrated by axial slice overlays on a standard magnetic resonance imaging template (D) and quantified by summed vectors of subregion z scores (E). GPe indicates globus pallidus externus; GPi, globus pallidus internus; HC, healthy controls; MRTM2, multilinear reference tissue modeling 2; PSP-CBS, PSP with predominant corticobasal syndrome; PSP-F, PSP with predominant frontal presentation; PSP-P, PSP with predominant parkinsonism; PSP-RS, PSP with Richardson syndrome; PUT, putamen; STN, subthalamic nucleus. aSignificantly differing regional 18F-PI-2620 binding among PSP subtypes.
Figure 4.
Figure 4.. Evaluation of 18F-PI-2620 for Detection of Progressive Supranuclear Palsy (PSP) at the Single-Patient Level
Semiquantitative classification of PSP target regions. A single region defined the scan as global positive. Visual classification was performed by dichotomous rating of the 18F-PI-2620 scan by 3 raters, who defined positivity/negativity for a PSP-like pattern. The bottom of each panel indicates the number of positive regions and total regions. AD indicates Alzheimer disease; ADD, dementia due to AD; DLPFC, dorsolateral prefrontal cortex; DMB, dorsal midbrain; DN, dentate nucleus; GPe, globus pallidus externus; GPi, globus pallidus internus; HC, healthy controls; MCI, mild cognitive impairment due to AD; MPFC, medial prefrontal cortex; MSA, multiple system atrophy; PD, Parkinson disease; PUT, putamen; PSP-CBS, PSP with predominant corticobasal syndrome; PSP-F, PSP with predominant frontal presentation; PSP-P, PSP with predominant parkinsonism; PSP-PGF, PSP with progressive gait freezing; PSP-RS, PSP with Richardson Syndrome; PSP-SL, PSP with predominant speech/language impairment; SN, substantia nigra; STN, subthalamic nucleus.
See this image and copyright information in PMC

Comment in

  • Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.
    Katzdobler S, Nitschmann A, Barthel H, Bischof G, Beyer L, Marek K, Song M, Wagemann O, Palleis C, Weidinger E, Nack A, Fietzek U, Kurz C, Häckert J, Stapf T, Ferschmann C, Scheifele M, Eckenweber F, Biechele G, Franzmeier N, Dewenter A, Schönecker S, Saur D, Schroeter ML, Rumpf JJ, Rullmann M, Schildan A, Patt M, Stephens AW, van Eimeren T, Neumaier B, Drzezga A, Danek A, Classen J, Bürger K, Janowitz D, Rauchmann BS, Stöcklein S, Perneczky R, Schöberl F, Zwergal A, Höglinger GU, Bartenstein P, Villemagne V, Seibyl J, Sabri O, Levin J, Brendel M; German Imaging Initiative for Tauopathies (GII4T). Katzdobler S, et al. Eur J Nucl Med Mol Imaging. 2023 Jan;50(2):423-434. doi: 10.1007/s00259-022-05964-w. Epub 2022 Sep 14. Eur J Nucl Med Mol Imaging. 2023. PMID: 36102964 Free PMC article.

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