MRI Measures of Disease Progression for PSP Clinical Trials

Last Updated Date: October 24, 2024

Authors: Simone P. Zehntner, Ph.D., Felix Carbonell, Ph.D., Jean-Phillipe Coutu, Ph.D., Alex P. Zijdenbos, Ph.D., Barry J. Bedell, M.D., Ph.D., for the 4-Repeat Tauopathy Neuroimaging Initiative and the Frontotemporal Lobar Degeneration Neuroimaging Initiative*

Key Takeaways

• Quantitative brain atrophy measures derived from anatomical MRI scans can facilitate the differential diagnosis of Progressive Supranuclear Palsy (PSP).
• We have used a fully-automated image processing "pipeline" purpose built for clinical trials for the computation of regional neuroanatomical volumes from 3D T1-weighted MR images of PSP participants in the 4RTNI Study.
• In the PSP natural history cohort, we found statistically significant MRI brain atrophy with a specific spatial pattern.
• Our approach requires substantially lower sample sizes to assess reduction of the observed atrophy compared to other quantitative image analysis tools.
• Our approach provides insights into regional brain atrophy in PSP, and may facilitate earlier readouts for disease-modifying therapeutics in PSP clinical trials.

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by movement, balance, speech, and eye movement difficulties. PSP is considered an atypical Parkinsonian syndrome, sharing some clinical characteristics with Parkinson's disease, but also having distinct pathology. PSP is a form of four-repeat tauopathy, characterized by the abnormal accumulation of tau protein in the brain. This accumulation leads to neuronal deterioration, particularly in the brainstem.

In this research study, we utilized our fully-automated image processing pipeline (PIANO™) to improve our understanding of reliable neuroimaging biomarkers that may provide a path to accurate and early diagnosis of PSP, as well as enable the rapid evaluation of novel therapeutics in clinical trials.

The PSP data used for analysis was obtained from the 4-Repeat Tauopathy Neuroimaging Initiative (4RTNI) database, while the cognitively normal healthy control (HC) subject data was obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database. 59 PSP and 117 healthy control participants were included in the analysis. All subjects were evaluated by MRI at baseline, 6 month follow-up, and 12 month follow-up visits, with clinical rating scales assessed at similar intervals.

We performed both MRPI and MRPI 2.0 measurements, voxelwise gray matter density analysis, deformation-based morphometry (DBM) analysis, and regional volumetric analysis. We also compared our results from PIANO™ to FreeSurfer, a platform widely used for MRI analysis by the academic research community. We performed sample size calculations at both 6 and 12 months for all measures.

When MRPI and MRPI 2.0 were applied to the PSP population, the MRPI ratios were significantly larger compared to other tauopathies, such as Corticobasal Degeneration (CBD) and Frontotemporal Dementia (FTD). The change over time of the planimetric metric in the PSP population also clearly illustrated the significant atrophy that occurs within the brainstem regions.

Voxelwise gray matter density changes over a 12 month period highlighted the rapid changes apparent in the PSP subjects. Statistical analysis of the voxelwise Jacobian determinants revealed statistically significant atrophy throughout the cerebellum, brainstem, and thalamus, along with the concurrent expansion of the ventricles and the sulci adjacent to the insula in the PSP subjects.

The brainstem, cerebellum, and subcortical regions showed a 2-4% reduction in volume over 12 months, compared to minimal changes observed in the same regions in the healthy control population. The ventricular, subcortical, and cerebellar regions showed highly significant volume loss even at 6 months.

As early as 6 months from baseline, less than 50 subjects per arm were estimated to be required to observe a 60% reduction in brain atrophy in the lateral ventricles, third ventricle, thalamus, and pallidum using the PIANO™-based volumetric analysis. As such, relatively quick insights into disease progression and potential therapeutic effects can be obtained. Sample size calculations based on the 12 month timepoint derived from FreeSurfer showed substantially higher sample size requirements for the same regional volumes. Similarly, the planimetric measurement of MRPI and MRPI 2.0 required 2-3 times the sample size compared to the PIANO™-based brainstem 3D volume assessments.

This novel work demonstrates that progressive, regional brain atrophy can be effectively assessed using automated quantitative analysis of MR images with reasonable sample sizes over a relatively short timeframe. As such, these imaging biomarkers look promising for evaluation of the efficacy of putative disease-modifying therapeutics in multi-center clinical trials.

Presentation Highlights

*Data used in preparation of this presentation were obtained from the 4-Repeat Tauopathy Neuroimaging Initiative (4RTNI) database and the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database. The investigators at 4RTNI and FTLDNI contributed to the design and implementation of 4RTNI and FTLDNI and/or provided data, but did not participate in analysis or writing of this report.