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

• Published in: Movement disorders Vol. 39; no. 8; pp. 1329 - 1342
• Main Authors: Franzmeier, Nicolai, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Panisset, Michael, Azulay, Jean‐Philippe, Mollenhauer, Brit, Benecke, Reiner, Höglinger, Günter, Lipp, Axel, Chan, Dennis, Burn, David, Lees, Andrew, Boxer, Adam, Honig, Lawrence, Zamrini, Edward, Lessig, Stephanie, Lew, Mark, Boeve, Brad, Ferrara, Joseph, Golbe, Lawrence, Leegwater‐Kim, Julie, Litvan, Irene, Grossman, Murray, Miller, Bruce L., Golbe, Lawrence I., Koestler, Mary, Van Deerlin, Viviana, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H., Gómez, J.C., Ybot, I., Aguilar, M., Boada, M., Höllerhage, M., Respondek, G., Knake, S., Maetzler, W., Kassubek, J., Burn, D.J., Morris, L., Ling, H., Strycharczuk, L., Antonini, Angelo, Martinez, Ernest Balaguer, Bang, Jee, Barrett, Matthew, Bordelon, Yvette, Boxer, Adam L., Brandt, Moritz, Castelnovo, Giovanni, Cudia, Paola, Evans, Andrew H., Finger, Elizabeth, Hall, Deborah, Houghton, David, Lang, Anthony E., Leigh, Peter Nigel, Moreno, Jose Luis Lopez‐Sendon, Piudo, Ma Rosario Luquin, Molho, Eric, Morris, Huw R., Magne, Fabienne Ory, Pavese, Nicola, Pokhabov, Dmitry, Prudlo, Johannes, Rodriguez‐Porcel, Federico, Rowe, James, Savitt, Joseph, Schulz, Joerg B., Seppi, Klaus, Shill, Holly, Steiger, Malcolm, Takigawa, Hiroshi, Tartaglia, Carmela, Toenges, Lars, Truong, Daniel, Wills, Anne‐Marie A., Xie, Tao, Yuasa, Tatsuhiko, Ersözlü, Ersin, Spruth, Eike Jakob, Spottke, Annika, Benennen, Bitte, Buerger, Katharina, Katzdobler, Sabrina, Jäck, Alexander, Kilimann, Ingo, Synofzik, Matthis, Hoffmann, Daniel C., Lüsebrink, Falk, Klockgether, Thomas, Höglinger, Günter U.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-08-2024; Wiley Subscription Services, Inc
• Subjects: Aged; atlas-based volumetry; Atrophy; Atrophy - pathology; Automation; Biomarkers; Brain - diagnostic imaging; Brain - pathology; Brain stem; Clinical trials; Clinical Trials as Topic - methods; Cohort Studies; Disease Progression; Female; Frontal lobe; Humans; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Mesencephalon; Middle Aged; Movement disorders; Neuroimaging; Neurologi; Neurology; Patients; progression; Progressive supranuclear palsy; Radiologi och bildbehandling; Radiology, Nuclear Medicine and Medical Imaging; staging system; Supranuclear Palsy, Progressive - diagnostic imaging; Supranuclear Palsy, Progressive - pathology; Ventricles (cerebral); atlas‐based volumetry; progression; clinical trials; staging system; progressive supranuclear palsy
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.29866

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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.