Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials-Reference-Cited by-同舟云学术

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

Published:2023-03-28 Issue:8 Volume:146 Page:3232-3242
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Street Duncan¹^ORCID,Jabbari Edwin²³^ORCID,Costantini Alyssa²³,Jones P Simon¹,Holland Negin¹,Rittman Timothy¹^ORCID,Jensen Marte T²³,Chelban Viorica⁴⁵^ORCID,Goh Yen Y⁴,Guo Tong²,Heslegrave Amanda J⁶⁷,Roncaroli Federico⁸,Klein Johannes C⁹¹⁰,Ansorge Olaf¹⁰,Allinson Kieren S J¹,Jaunmuktane Zane²¹¹¹²,Revesz Tamas¹¹¹²,Warner Thomas T¹¹¹²^ORCID,Lees Andrew J¹¹¹²^ORCID,Zetterberg Henrik⁶⁷¹³¹⁴¹⁵,Russell Lucy L⁶,Bocchetta Martina¹⁶¹⁷^ORCID,Rohrer Jonathan D⁶,Burn David J¹⁸,Pavese Nicola¹⁹,Gerhard Alexander²⁰²¹^ORCID,Kobylecki Christopher²⁰²²,Leigh P Nigel²³,Church Alistair²⁴,Hu Michele T M¹⁰²⁵,Houlden Henry²³⁴^ORCID,Morris Huw²³^ORCID,Rowe James B¹²⁶

Affiliation:

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

Abstract

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.

Funder

PROSPECT

MSA Trust

Wellcome Trust

NIHR

Cambridge Brain Bank

Department of Health and Social Care

Medical Research Council

UCLH

Reta Lila Weston Institute for Neurological Studies

MRC

UK Dementia Research Institute