Multicenter Study

. 2023 Aug 1;146(8):3232-3242.

doi: 10.1093/brain/awad105.

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials

Duncan Street¹, Edwin Jabbari^{2

3}, Alyssa Costantini^{2

3}, P Simon Jones¹, Negin Holland¹, Timothy Rittman¹, Marte T Jensen^{2

3}, Viorica Chelban^{4

5}, Yen Y Goh⁴, Tong Guo², Amanda J Heslegrave^{6

7}, Federico Roncaroli⁸, Johannes C Klein^{9

10}, Olaf Ansorge¹⁰, Kieren S J Allinson¹, Zane Jaunmuktane^{2

11

12}, Tamas Revesz^{11

12}, Thomas T Warner^{11

12}, Andrew J Lees^{11

12}, Henrik Zetterberg^{6

7

13

14

15}, Lucy L Russell⁶, Martina Bocchetta^{16

17}, Jonathan D Rohrer⁶, David J Burn¹⁸, Nicola Pavese¹⁹, Alexander Gerhard^{20

21}, Christopher Kobylecki^{20

22}, P Nigel Leigh²³, Alistair Church²⁴, Michele T M Hu^{10

25}, Henry Houlden^{2

3

4}, Huw Morris^{2

3}, James B Rowe^{1

26}

Affiliations

¹ University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, CB2 OQQ, UK.
² Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
³ Movement Disorders Centre, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁴ Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁵ Neurobiology and Medical Genetics Laboratory, 'Nicolae Testemitanu' State University of Medicine and Pharmacy, Chisinau 2004, Republic of Moldova.
⁶ Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁷ UK Dementia Research Institute, University College London, London, W1T 7NF, UK.
⁸ Geoffrey Jefferson Brain Research Centre, Division of Neuroscience, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M6 8HD, UK.
⁹ Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
¹⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
¹¹ Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
¹² Reta Lila Weston Institute, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
¹³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 30 Mölndal, Sweden.
¹⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Salhgrenska Academy at the University of Gothenburg, 413 45 Goteborg, Sweden.
¹⁵ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Shatin, N.T., Hong Kong, China.
¹⁶ Centre for Cognitive and Clinical Neuroscience, Division of Psychology, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, London, UB8 3PH, UK.
¹⁷ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
¹⁸ Faculty of Medical Sciences, Newcastle University, Newcastle, NE2 4HH, UK.
¹⁹ Clinical Ageing Research Unit, Newcastle University, Newcastle, NE4 5PL, UK.
²⁰ Division of Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, N20 3LJ, UK.
²¹ Departments of Geriatric Medicine and Nuclear Medicine, Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen, 45356 Essen, Germany.
²² Department of Neurology, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, Salford, M13 9NQ, UK.
²³ Department of Neuroscience, Brighton and Sussex Medical School, Brighton, BN1 9PX, UK.
²⁴ Department of Neurology, Royal Gwent Hospital, Newport, NP20 2UB, UK.
²⁵ Department of Physiology, Anatomy and Genetics, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3QU, UK.
²⁶ Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, UK.

PMID: 36975168
PMCID: PMC10393398
DOI: 10.1093/brain/awad105

Multicenter Study

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials

Duncan Street et al. Brain. 2023.

. 2023 Aug 1;146(8):3232-3242.

doi: 10.1093/brain/awad105.

Authors

Affiliations

¹ University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, CB2 OQQ, UK.
² Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
³ Movement Disorders Centre, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁴ Department of Neuromuscular Diseases, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁵ Neurobiology and Medical Genetics Laboratory, 'Nicolae Testemitanu' State University of Medicine and Pharmacy, Chisinau 2004, Republic of Moldova.
⁶ Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁷ UK Dementia Research Institute, University College London, London, W1T 7NF, UK.
⁸ Geoffrey Jefferson Brain Research Centre, Division of Neuroscience, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M6 8HD, UK.
⁹ Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
¹⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
¹¹ Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
¹² Reta Lila Weston Institute, University College London, Queen Square Institute of Neurology, London, WC1N 3BG, UK.
¹³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 30 Mölndal, Sweden.
¹⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Salhgrenska Academy at the University of Gothenburg, 413 45 Goteborg, Sweden.
¹⁵ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Shatin, N.T., Hong Kong, China.
¹⁶ Centre for Cognitive and Clinical Neuroscience, Division of Psychology, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, London, UB8 3PH, UK.
¹⁷ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
¹⁸ Faculty of Medical Sciences, Newcastle University, Newcastle, NE2 4HH, UK.
¹⁹ Clinical Ageing Research Unit, Newcastle University, Newcastle, NE4 5PL, UK.
²⁰ Division of Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, N20 3LJ, UK.
²¹ Departments of Geriatric Medicine and Nuclear Medicine, Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen, 45356 Essen, Germany.
²² Department of Neurology, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, Salford, M13 9NQ, UK.
²³ Department of Neuroscience, Brighton and Sussex Medical School, Brighton, BN1 9PX, UK.
²⁴ Department of Neurology, Royal Gwent Hospital, Newport, NP20 2UB, UK.
²⁵ Department of Physiology, Anatomy and Genetics, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3QU, UK.
²⁶ Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, UK.

PMID: 36975168
PMCID: PMC10393398
DOI: 10.1093/brain/awad105

Abstract

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.

Keywords: clinical trials; corticobasal syndrome; multiple system atrophy; progressive supranuclear palsy; sample size.

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Conflict of interest statement

H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). N.P. has received consultancy fees and speaker fees from Bial, AbbVie, Roche, 4D Pharma, Britannia. M.H. has received funding/grant support from Parkinson’s UK, Oxford NIHR BRC, University of Oxford, CPT, Lab10X, NIHR, Michael J Fox Foundation, H2020 European Union, GE Healthcare and the PSP Association. She also received payment for Advisory Board attendance/consultancy for Biogen, Roche, Sanofi Aventis, CuraSen Therapeutics, Evidera, Manus Neurodynamica, Lundbeck. H.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche and Amylyx; lecture fees/honoraria—BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. H.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140).

J.B.R. has research grants unrelated to the current work from AstraZeneca, Janssen, Lilly, GSK via the Dementias Platform UK; and has provided consultancy unrelated to the current work, to Asceneuron, Astex, Curasen, UCB, SV Health, WAVE and Alzheimer Research UK. All other authors report no competing interests related to this work.

The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Figures

**Figure 1**
**Sankey plot of change in diagnosis between baseline** **and study end point.** 4RT = four-repeat tau; AD = Alzheimer’s disease; CBS = corticobasal syndrome; IDT = indeterminate; MSA-C = multiple system atrophy cerebellar variant; MSA-P = multiple system atrophy parkinsonian variant; PSP = progressive supranuclear palsy; PSP-C = PSP-cortical; PSP-RS = PSP-Richardson’s syndrome; PSP-SC = PSP-subcortical.

**Figure 2**
**Survival analysis from symptom onset to death**. Analysis was performed using a Cox regression model split according to diagnostic groups with associated number at risk tables below each plot. (A) Indeterminate (APS), corticobasal syndrome (CBS), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) groups. (B) PSP-cortical (PSP-C), PSP-subcortical (PSP-SC), and PSP-Richardson’s syndrome (PSP-RS) groups. (C) CBS-four-repeat tau (CBS-4RT), CBS-Alzheimer’s disease (CBS-AD) and CBS-indeterminate (CBS-IDT) groups. (D) MSA-cerebellar (MSA-C) and MSA-parkinsonism (MSA-P) groups.

**Figure 3**
**Estimated sample size and bootstrapped confidence interval plots by final diagnosis at group level (*left*) and by intention to treat at group level (*right*)**. ACE III = Addenbrookes Cognitive Examination III; CBD-FS = Corticobasal Degeneration Functional Scale; CBI-R = Cambridge Behavioural Inventory Revised; CBS = corticobasal syndrome; mPSPRS = modified Progressive Supranuclear Palsy Rating Scale; MSA = multiple system atrophy; PSP = progressive supranuclear palsy; PSP QoL = PSP Quality of Life Scale; PSPRS = PSP rating scale; SEADL = Schwab and England Activities of Daily Living Scale; UMSARS = Unified MSA Rating Scale; UPDRS = Unified Parkinson’s Disease Rating Scale.

**Figure 4**
**Estimated sample size and bootstrapped confidence interval plots by final diagnosis and phenotype (*left*); and by intention to treat and phenotype (*right*)**. 4RT = 4-repeat tau; AD = Alzheimer disease; ACE III = Addenbrookes Cognitive Examination III; CBD-FS = Corticobasal Degeneration Functional Scale; CBI-R = Cambridge Behavioural Inventory Revised; CBS = corticobasal syndrome; ECAS = Edinburgh Cognitive and Behavioural Screen; FTD-FRS = Frontotemporal Dementia Rating Scale; IDT = indeterminate; MoCA = Montreal Cognitive Assessment; mPSPRS = modified Progressive Supranuclear Palsy Rating Scale; MSA = multiple system atrophy; MSA QoL = MSA Quality of Life Scale; PSP = progressive supranuclear palsy; PSP QoL = PSP Quality of Life Scale; PSPRS = PSP Rating Scale; SD = standard deviation; SEADL = Schwab and England Activities of Daily Living Scale; UPDRS = Unified Parkinson’s Disease Rating Scale; UMSARS = Unified MSA Rating Scale.

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References

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Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials

Affiliations

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous