Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants.
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Ghosh, Boyd CP
Oxford University Press (OUP)
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Street, D., Malpetti, M., Rittman, T., Ghosh, B. C., Murley, A. G., Coyle-Gilchrist, I., Passamonti, L., & et al. (2021). Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants.. Brain communications, 3 (3), fcab206. https://doi.org/10.1093/braincomms/fcab206
Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardson’s syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next two years. However, many people with progressive supranuclear palsy do not meet eligibility criteria for these clinical trials. Understanding clinical progression with different phenotypes would improve trial design and enhance the accuracy of risk-benefit and cost-benefit assessments of new treatments for progressive supranuclear palsy. We set out to determine rates of motor and cognitive progression of possible, probable and definite progressive supranuclear palsy, with different phenotypes, from a representative cohort in a regional United Kingdom healthcare service. Longitudinal clinical data from people with Richardson’s syndrome and variant phenotypes were analysed using linear mixed-modelling, using both the full and modified versions of the Progressive Supranuclear Palsy Rating Scale, Mini-Mental State Examination, and the revised Addenbrooke’s Cognitive Examination. Subgroup analyses considered patients meeting recent phase II trial entry criteria and patients with neuropathological confirmation. 227 patients (male=59%, mean age [±Standard Deviation], 71.8[±7.0] years) were followed for a mean 21.6[±15.6] months. One hundred and seventy-four (77%) had Richardson’s syndrome at the outset, twenty-five had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and twenty-eight had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardson’s syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 vs -0.9/year, p=.005) and revised Addenbrooke’s Cognitive Examination (-5.3 vs -3.0/year, p=.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 vs 7.1/year, p=0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 vs 2.3/year, p=.4). However, for those with more than one years’ follow-up, a significant difference was observed between Richardson’s syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 vs 6.3/year, p=.04). Survival was longer in variant phenotypes than Richardson’s syndrome (7.3[±3.9] vs 5.6[±2.0] years, p=.02). Pathologically confirmed cases (n=49) supported these findings. Patients meeting basic trial-eligibility criteria (n=129) progressed faster on the Progressive Supranuclear Palsy Rating Scale than trial-not-eligible patients (10.1 vs 6.1/year, p=.001). In conclusion, phenotypes other than Richardson’s syndrome show slower progression and longer survival. Trial criteria do not select representative progressive supranuclear palsy cases. This has implications for trial design, and application of trial results to clinically more diverse patient populations.
This study was co-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge (BRC-1215-20014) and the Cambridge Brain Bank; the Holt Fellowship (RG86564); the Medical Research Council (MR/P01271X/1; SUAG051/G101400 and SUAG004/051/RG91365); Fitzwilliam College and the Cambridge University Centre for Parkinson-plus (RG95450).
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
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External DOI: https://doi.org/10.1093/braincomms/fcab206
This record's URL: https://www.repository.cam.ac.uk/handle/1810/325410
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/