Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials

the AL-108-231 Investigators, the Tauros MRI Investigators, the PASSPORT Study Group, the DESCRIBE-PSP Group

doi:10.1002/mds.29866

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials

the AL-108-231 Investigators, the Tauros MRI Investigators, the PASSPORT Study Group, the DESCRIBE-PSP Group

Neurology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Methods: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects.

Original language	English (US)
Pages (from-to)	1329-1342
Number of pages	14
Journal	Movement Disorders
Volume	39
Issue number	8
DOIs	https://doi.org/10.1002/mds.29866
State	Published - Aug 2024

Funding

H\u2010J.H. has used atlas\u2010based volumetric MRI analysis in industry\u2010sponsored research projects. M.K. serves as a consultant for AbbVie and Stada; received honoraria for scientific presentations from AbbVie, Ever, and Licher, and was funded by the German Parkinson's Disease Association, Pitzer Foundation, Petermax\u2010M\u00FCller Foundation, and MHH Plus Foundation. J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, Merck, Roche, TEVA, and Zambon; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers, and W. Kohlhammer GmbH medical publishers; and is inventor of a patent \u2018Oral Phenylbutyrate for Treatment of Human 4\u2010Repeat Tauopathies\u2019 (EP 23156122.6) 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 of a patent \u2018Pharmaceutical Composition and Methods of Use\u2019 (EP 22159408.8) filed by MODAG GmbH. A.L.B. has served as a paid consultant to AGTC, Alchemab, Alector, Alzprotect, Amylyx, Arkuda, Arrowhead, Arvinas, Aviado, Eli Lilly, GSK, Humana, Merck, Modalis, Muna, Oligomerix, Oscotec, Pfizer, Roche, Switch, Transposon, and UnlearnAI. His institution received research support from Biogen and Eisai for him serving as a site investigator for clinical trials, as well as from Regeneron. He has received research support from the National Institutes on Aging: NIH U19AG063911, R01AG078457, R01AG073482, R56AG075744, R01AG038791, RF1AG077557, P01AG019724, R01AG071756, U24AG057437; Rainwater Charitable Foundation, Bluefield Project to Cure FTD, GHR Foundation, Alzheimer's Association, Association for Frontotemporal Degeneration, Gates Ventures, Alzheimer's Drug Discovery Foundation, UCSF Parkinson's Spectrum Disorders Center, and the University of California Cures AD Program. G.H. participated in industry\u2010sponsored research projects from AbbVie, Biogen, Biohaven, Novartis, Roche, Sanofi, and UCB; has ongoing research collaborations with Roche, UCB, and AbbVie; serves as a consultant for AbbVie, Alzprotect, Amylyx, Aprineua, Asceneuron, Bayer, Bial, Biogen, Biohaven, Epidarex, Ferrer, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, Servier, Takeda, Teva, and UCB; received honoraria for scientific presentations from AbbVie, Bayer, Bial, Biogen, Bristol Myers Squibb, Kyowa Kirin, Pfizer, Roche, Teva, UCB, and Zambon. G.H. was funded 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 \u2013 ID 390857198), European Joint Programme on Rare Diseases (Improve\u2010PSP), Nieders\u00E4chsisches Ministerium f\u00FCr Wissenschaft und Kunst (MWK)/VolkswagenStiftung (Nieders\u00E4chsisches Vorab), Petermax\u2010M\u00FCller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies), and the German Society for Parkinson's and Movement Disorders (DPG): ProAPS.

Keywords

atlas-based volumetry
clinical trials
progression
progressive supranuclear palsy
staging system

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/mds.29866

Cite this

@article{72df7794aa4b425a8d00ef28971f6553,

title = "Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials",

abstract = "Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Methods: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects.",

keywords = "atlas-based volumetry, clinical trials, progression, progressive supranuclear palsy, staging system",

author = "{the AL-108-231 Investigators, the Tauros MRI Investigators, the PASSPORT Study Group, the DESCRIBE-PSP Group} and Andrea Quattrone and Nicolai Franzmeier and Huppertz, {Hans J{\"u}rgen} and Martin Klietz and Roemer, {Sebastian N.} and David Williams and Lafontaine, {Anne Louise} and Connie Marras and Mandar Jog and Michael Panisset and Anthony Lang and Lesley Parker and Stewart, {Alistair J.} and Corvol, {Jean Christophe} and Azulay, {Jean Philippe} and Philippe Couratier and Brit Mollenhauer and Stefan Lorenzl and Albert Ludolph and Reiner Benecke and G{\"u}nter H{\"o}glinger and Axel Lipp and Heinz Reichmann and Dirk Woitalla and Dennis Chan and Adam Zermansky and David Burn and Andrew Lees and Adam Boxer and Miller, {Bruce L.} and Lobach, {Iryna V.} and Erik Roberson and Lawrence Honig and Edward Zamrini and Rajesh Pahwa and Yvette Bordelon and Erika Driver-Dunkley and Stephanie Lessig and Mark Lew and Kyle Womack and Brad Boeve and Joseph Ferrara and Argyle Hillis and Daniel Kaufer and Rajeev Kumar and Tao Xie and Steven Gunzler and Theresa Zesiewicz and Praveen Dayalu and Danny Bega",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2024",

month = aug,

doi = "10.1002/mds.29866",

language = "English (US)",

volume = "39",

pages = "1329--1342",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley & Sons Inc.",

number = "8",

}

TY - JOUR

T1 - Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials

AU - the AL-108-231 Investigators, the Tauros MRI Investigators, the PASSPORT Study Group, the DESCRIBE-PSP Group

AU - Quattrone, Andrea

AU - Franzmeier, Nicolai

AU - Huppertz, Hans Jürgen

AU - Klietz, Martin

AU - Roemer, Sebastian N.

AU - Williams, David

AU - Lafontaine, Anne Louise

AU - Marras, Connie

AU - Jog, Mandar

AU - Panisset, Michael

AU - Lang, Anthony

AU - Parker, Lesley

AU - Stewart, Alistair J.

AU - Corvol, Jean Christophe

AU - Azulay, Jean Philippe

AU - Couratier, Philippe

AU - Mollenhauer, Brit

AU - Lorenzl, Stefan

AU - Ludolph, Albert

AU - Benecke, Reiner

AU - Höglinger, Günter

AU - Lipp, Axel

AU - Reichmann, Heinz

AU - Woitalla, Dirk

AU - Chan, Dennis

AU - Zermansky, Adam

AU - Burn, David

AU - Lees, Andrew

AU - Boxer, Adam

AU - Miller, Bruce L.

AU - Lobach, Iryna V.

AU - Roberson, Erik

AU - Honig, Lawrence

AU - Zamrini, Edward

AU - Pahwa, Rajesh

AU - Bordelon, Yvette

AU - Driver-Dunkley, Erika

AU - Lessig, Stephanie

AU - Lew, Mark

AU - Womack, Kyle

AU - Boeve, Brad

AU - Ferrara, Joseph

AU - Hillis, Argyle

AU - Kaufer, Daniel

AU - Kumar, Rajeev

AU - Xie, Tao

AU - Gunzler, Steven

AU - Zesiewicz, Theresa

AU - Dayalu, Praveen

AU - Bega, Danny

PY - 2024/8

Y1 - 2024/8

N2 - Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Methods: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects.

AB - Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Methods: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects.

KW - atlas-based volumetry

KW - clinical trials

KW - progression

KW - progressive supranuclear palsy

KW - staging system

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DO - 10.1002/mds.29866

M3 - Article

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JO - Movement Disorders

JF - Movement Disorders

IS - 8

ER -

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials

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