Clinical correlates of longitudinal brain atrophy in progressive supranuclear palsy
Introduction
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by early falls, supranuclear ophthalmoplegia, axial rigidity and executive dysfunction [1]. Clinical diagnosis of the most common presentation of PSP, Richardson's syndrome, is highly predictive of abnormal tau protein deposition in neurons and glia at autopsy [2], [3]. Potential therapies are entering early clinical trials. To achieve regulatory approval, therapeutics must demonstrate treatment-associated benefits on clinical or functional outcomes in a placebo controlled trial, requiring large numbers and extended longitudinal follow up. Biomarkers such as volumetric magnetic resonance imaging (vMRI) may have advantages over clinical measures from sensitivity to change and precision of measurement, leading to more efficient trials. Moreover, biomarkers may provide data supportive of a disease modifying effect [4]. In multiple sclerosis, incorporation of MRI as a biomarker has allowed more efficient determination of proof of concept for new therapeutics in phase 2 trials [5].
Previous cross-sectional vMRI studies demonstrated atrophy of the midbrain, premotor cortex, basal ganglia and thalamus in PSP [6], [7]. Longitudinal studies have explored rates of brain atrophy, but were typically performed in single centers with relatively small cohorts, potentially limiting their findings' relevance to multicenter clinical trials [8], [9], [10], [11], [12].
To examine the utility of vMRI for measuring disease progression in multicenter clinical trials, we used longitudinal vMRI data from the AL-108-231 clinical trial of davunetide for PSP [13]. The goals were: 1) power of standard vMRI measurements to capture disease progression in a multicenter PSP clinical trial, 2) how regional vMRI changes relate to changes in clinical ratings and neuropsychological scores, and 3) value of baseline clinical measures in predicting atrophy rate.
Section snippets
Participants
The AL-108-231 clinical trial was a phase 2/3 double-blind, placebo-controlled trial, completed in 2012, conducted at 48 centers on three continents that enrolled 313 patients with PSP randomized 1:1 to davunetide (a neurotrophic peptide) or placebo for one year. 198 individuals with baseline and week 52 MRI data, complete clinical data including the primary outcome measures: Progressive Supranuclear Palsy Rating Scale (PSPRS) [14] and Schwab and England Activities of Daily Living scales
Demographics
Patient characteristics are shown in Table 1. The baseline demographic and clinical scale values of this group were similar to the overall study population [13]. In addition, the primary outcomes at week 52 for this study were no different compared to overall study population at the end of trial (data not shown) [13]. Clinical progression over 1 year was measured by an increase of PSPRS 9.6 ± 0.6 points and SEADL declined 16 ± 1%. Cognitive function worsened over one year while mood measured by
Discussion
Using data from a large, multicenter, international clinical trial, we show that longitudinal vMRI measurements of regional brain atrophy in PSP are feasible and sensitive to disease progression over one year, but only modestly correlate with change measured by clinical scales and neuropsychology testing. Whole brain, midbrain atrophy and ventricular volume changes were associated with clinical disease progression measured by PSPRS, SEADL, GDS and CGIC, and cognitive decline measured by RBANS
Study funding
R01AG038791, U54NS092089, Tau Consortium and Allon Therapeutics.
Authorship roles
Richard M. Tsai, MD, MBA. [email protected]: Corresponding author, drafting and revising manuscript, analysis and interpretation of data.
Iryna Lobach, PhD. [email protected]: Analysis and interpretation of data.
Jee Bang, MD. [email protected]: Analysis and interpretation of data.
Jennifer L. Whitwell, PhD. [email protected]: Revising the manuscript for content.
Matthew L. Senjem. [email protected]: Analysis and interpretation of data.
Clifford R. Jack, Jr., MD. [email protected]
Funding sources
R01AG038791, U54NS092089, Tau Consortium and Allon Therapeutics.
Conflicts of interest
Drs. Tsai, Lobach, Bang, Whitwell, Jack, Rosen, Miller and Mr. Senjem report no conflicts of interest.
Dr. Boxer receives research support from Avid, Biogen, Bristol Myers Squibb, C2N Diagnostics, Cortice Bioscienecs, Eli Lilly, Forum Pharmaceuticals, Genentech and TauRx. He has served as a consultant for Asceneuron, Ipierian, Isis, Janssen and Merck. He has stock/options in Alector and Delos.
Acknowledgements
This work was supported by the National Institute of Health/National Institute of Aging (grant numbers K24 AG045333-01, R01 AG032306). We would like to thank The AL-108-231 Study Group: Australia: David Williams; Canada: Anne Louise Lafontaine, Connie Marras, Mandar Jog, Michael Panisset, Anthony Lang, Lesley Parker, Alistair J. Stewart; France: Jean-Christophe Corvol, Jean-Philippe Azulay, Philippe Couratier; Germany: Brit Mollenhauer, Stefan Lorenzl, Albert Ludolph, Reiner Benecke, Gunter
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