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Supplementary data is available online at https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad105/7091433#supplementary-data . Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout. Copyright © The Author(s) 2023. The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer’s disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression. The Progressive Supranuclear Palsy–Corticobasal Syndrome–Multiple System Atrophy (PROSPECT-M-UK) study is supported by grants for PROSPECT, cerebrospinal fluid biomarker measurements, and PROSPECT magnetic resonance imaging and Sara Koe Fellowship grants from the PSP Association UK, CBD Solutions, the MSA Trust, the Wellcome Trust (103838; 220258); the NIHR Cambridge Biomedical Research Centre and Cambridge Brain Bank (BRC 1215-20014; NIHR203312: The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care); Cambridge Centre for Parkinson-Plus; Medical Research Council (SUAG/092 116768); and the NIHR UCLH Biomedical Research Centre. Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the MRC. The fluid biomarker measurements were supported in part by the UK Dementia Research Institute at UCL and a multiuser equipment grant from Wellcome Trust. The Cambridge Brain Bank is part of the Cambridge Human research Tissue Bank funded by the Biomedical Research Council. The Oxford Brain Bank is supported by the MRC, Brains for Dementia Research (Alzheimer’s Society and Alzheimer’s Research UK), and the NIHR Oxford Biomedical Research Centre. In addition, this study was supported by the Medical Research Council (MRC 548211) (Dr Jabbari); the Association of British Neurologists Clinical Research Training Fellowships (Dr Holland, Dr Goh and Dr Chelban); the MSA Trust (Dr Chelban, Dr Goh); Guarantors of Brain (Dr Chelban); CBD Solutions (Dr Revesz, and Dr Morris); the NIHR Oxford Health Clinical Research Facility (Dr Klein); the NIHR Queen Square Biomedical Research Centre based at UCLH (Dr Revesz and Dr Jaunmuktane) a Wallenberg Academy fellowship (Dr Zetterberg); the Monument Trust Discovery Award from Parkinson’s UK (Dr Hu). Dr Bocchetta is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). Dr Bocchetta’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Professor Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Professor Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. Professor Roncaroli’s work is supported by The Manchester Brain Bank, which is part of BDR, jointly funded by Alzheimer’s Society and Alzheimer’s Research UK. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission, under a Creative Commons Attribution 4.0 International License.