Volumetric MRI & Corticobasal Degeneration (CBD)

Last Updated Date: November 8, 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 from anatomical MRI scans can aid in the diagnosis of Corticobasal Degeneration (CBD).
• 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 and diffusion MRI scans of CBD participants in the 4RTNI Study.
• In the CBD natural history cohort, we identified a distinct spatial pattern of significant brain atrophy and diffusion MRI changes.
• Our approach requires substantially lower sample sizes to assess reduction of the observed atrophy and diffusion MRI metrics compared to other quantitative image analysis tools.
• Our approach offers insights into regional brain atrophy and microstructural changes, and potentially facilitates early readouts for disease-modifying treatments for CBD in clinical trials.

Corticobasal Degeneration (CBD) is a rare neurodegenerative disorder marked by abnormal tau protein buildup, causing neuronal degeneration, particularly in the cerebral cortex. CBD shares many symptoms. including motor disturbances, cognitive impairment, dystonia, apraxia, and alien limb syndrome with other Parkinsonian disorders, and CBD is often misdiagnosed as Progressive Supranuclear Palsy (PSP). Accurate neuroimaging biomarkers can aid in the early diagnosis and evaluation of treatments.

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 CBD, as well as enable the rapid evaluation of novel therapeutics in clinical trials. 

The CBD and PSP data used for analysis was obtained from the 4-Repeat Neuroimaging Initiative (4RTNI) database, while the cognitively normal healthy control (HC) subject data was obtained from the Frontotemporal Lobar Degeneration Neuroimaging (FTLDNI) Initiative database. 48 CBD, 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 voxelwise gray matter density assessments derived from 3D T1-weighted MR images to investigate changes over a 12 month period. This exploratory analysis revealed a reduction in gray matter density throughout the cortex in the CBD subjects, both at baseline compared to controls, as well as the regions changing over 12 months, while distinctly different patterns of cortical atrophy were observed compared to PSP subjects.

Quantitative regional atrophy assessment comparing CBD and PSP subjects illustrated the disease-specific patterns of atrophy, with the cerebellar peduncles and brainstem the PSP subjects having greater atrophy and demonstrating a 2-4% reduction in volume over this time period while having only limited cortical atrophy. In contrast, in the cortical regions (sensory, motor, frontal, and parietal), the CBD subjects showed a greater rate of atrophy (3-5% over 12 months). 

Even as early as 6 months, fewer than 50 subjects per arm were estimated to be required to observe a 60% slowing of the observed brain atrophy in the lateral and third ventricles of CBD subjects using PIANO™-based volumetric analysis. The sample size estimations at 12 months required less than 60 subjects to detect a 60% reduction of the observed brain atrophy across all regions. Sample size calculations based on the 12 month timepoint for volumes derived from FreeSurfer showed substantially higher sample size requirements for the same brain regions.

Voxelwise and ROI-based changes derived from diffusion MRI scans over a 12 month period highlighted the rapid changes apparent in the CBD subjects. The exploratory voxelwise analysis highlighted the dramatic changes in the white matter, particularly parietal white matter, and cortical regions in the CBD subjects. A number of white matter, cortical, and subcortical regions require fewer than 50 subjects to detect a 60% or 80% reduction of the observed change in a treated group compared to an untreated group.

The graph of sample size per arm vs. percent reduction in diffusion MRI metric change highlights a number of white matter, cortical, and subcortical regions that require fewer than 50 subjects to detect a 60% or 80% reduction of the observed change in a treated group compared to an untreated group. As early 6 months, less than 50 subjects per arm were estimated to be required to observe a 80% slowing of the diffusion MRI changes in the corpus callosum, parietal white matter, and several cortical and subcortical regions using PIANO™-based analysis.

This novel work demonstrates that progressive regional brain atrophy and microstructural changes in gray and white matter 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 appear to be promising for evaluation of the efficacy of putative disease-modifying therapeutics for CBD 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.