Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2019 Mar:60:138-145.
doi: 10.1016/j.parkreldis.2018.08.025. Epub 2018 Sep 4.

Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Claire Brittain  1 , Andrew McCarthy  2 , Michael C Irizarry  3 , Dana McDermott  4 , Kevin Biglan  3 , Günter U Höglinger  5 , Stefan Lorenzl  6 , Teodoro Del Ser  7 , Adam L Boxer  4 ; AL-108-231 Study Group; PROPSPERA investigators; 4RNTI-1authors; Tau Restoration on PSP (TAUROS) Investigators
Collaborators, Affiliations
Clinical Trial

Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Claire Brittain et al. Parkinsonism Relat Disord. 2019 Mar.

Abstract

Background: Progressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.

Objectives: To determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.

Methods: Multicenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.

Results: The earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.

Conclusion: The PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Keywords: Corticobasal syndrome; Interactive visualizations; PSP rating scale; Predictive models; Progressive supranuclear palsy.

PubMed Disclaimer

Conflict of interest statement

Financial Disclosure/Conflict of Interest: KB, CB, MI, and AM were employees of, and stockholders in, Eli Lilly and Company at the time of writing. Eli Lilly contracted with inVentiv Health Clinical for editorial support of this document.

Financial Disclosures KB, CB, MI, and AM are employees of, and stockholders in, Eli Lilly and Company.

DM receives income through UC San Francisco and has no other financial parties to disclose.

ALB receives research support from the NIH (R01AG038791, U54NS092089), the University of California, the Tau Consortium, CBD Solutions, the Bluefield Project to Cure FTD, the Alzheimer’s Association and the following companies: Avid, Biogen, Bristol Myers Squibb, C2N Diagnostics, Cortice Biosciences, Eli Lilly, Forum Pharmaceuticals, Genentech, Roche and TauRx; has served as a consultant for Abbvie, Asceneuron, Celgene, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Samumed, Toyama and UCB; serves on a Data and Safety Monitoring Board for Neurogenetics Pharmaceuticals; has stock and/or options in Aeton, Alector and Delos.

TDS has not received research grants, has not served as a consultant and has not participated in any Advisory Board during the last year. He has no Intellectual Property Rights, Royalties, Contracts or Grants. He has stock in Pharmamar.

SL has received research grants from the Bavarian State and the Deutsche Stifterverband. He has received honoraria for presentations from UCB and Abbvie. He has not served as a consultant and has not participated in any Advisory Board during the last year. He has no Intellectual Property Rights, Royalties, Contracts stock ownerships.

GH has served on the advisory boards for AbbVie, Alzprotect, Asceneuron, Bristol-Myers Squibb, Novartis, Roche, Sellas Life Sciences Group, UCB; has received honoraria for scientific presentations from Abbvie, Roche, Teva, UCB, has received research support from CurePSP, the German Academic Exchange Service (DAAD), German Parkinson’s Disease Foundation (DPG), German PSP Association (PSP Gesellschaft), German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF), International Parkinson’s Fonds (IPF), the Sellas Life Sciences Group; has received institutional support from the German Center for Neurodegenerative Diseases (DZNE).

GH was funded by the Deutsche Forschungsgemeinschaft (DFG, HO2402/6–2 & Munich Cluster for Systems Neurology SyNergy).

Figures

Figure 1.
Figure 1.. Proportional Odds Models - Sequence of Decline of PSP Rating Scale Subscores for Mild, Moderate, and Severe Impairment as PSP Rating Scale Total Score Worsens - 4 PSP Studies Combined
Note: Four snapshots of PSP disease progression using the online graphic; each graphic shows the percent of patients that are contained within each category of domain impairment (e.g. no/mild, moderate, or severe). Abbreviation: PSP, progressive supranuclear palsy. Link to online version: https://pspmodel.shinyapps.io/PSP_Progression/
Figure 2.
Figure 2.. Proportional Odds Models – Probability of Start of Mild Impairment for Each PSP Rating Scale Domain Subscore as PSP Rating Scale Total Score Worsens – PSP (all 4 studies) vs CBS (4RTNI) (upper panel), and as CGIds and SEADL Worsen – AL-108–231, 4RTNI, and TAUROS Studies Combined (lower panel)
Abbreviation: CBS, corticobasal syndrome; CGIds, Clinical Global Impression of Disease Severity; PSP, progressive supranuclear palsy; SEADL, Schwaab and England Activities of Daily Living. Dashed line represents the average score of a patient entering a clinical trial (Table 2); PSPRS=38, SEADL=55, CGIds=4 for PSP patients and 28 for CBS patients. Note: Link to online version with 95% Cis: https://pspmodel.shinyapps.io/PSP_Progression/
Figure 3.
Figure 3.. Longitudinal Model of Change from Baseline PSP Rating Scale Subscores and Total Score of Placebo PSP-Richardson’s Syndrome Patients (AL-108–231 and 4RTNI)
Note: Link to online version with 95% Cis: https://pspmodel.shinyapps.io/PSP_Progression/
See this image and copyright information in PMC

References

    1. Coyle-Gilchrist I, Dick K, Patterson K et al. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology. 2016; May 3; 86(18): 1736–1743. - PMC - PubMed
    1. Golbe LI, Davis PH, Schoenberg BS, Duvoisin RC. Prevalence and natural history of progressive supranuclear palsy. Neurology. 1988; 38:1031–1034. - PubMed
    1. Kouri N, Ross OA, Dombroski B, et al. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun 2015: 16: 7247. - PMC - PubMed
    1. Tsai RM and Boxer AL. Clinical Trials: past, current and future for atypical parkinsonian syndromes. Semin Neurol 2014; 34: 225–234. - PMC - PubMed
    1. Stamelou M, Höglinger G. A Review of Treatment Options for Progressive Supranuclear Palsy. CNS Drugs 2016; 30: 629–636. - PubMed

Publication types