Frontotemporal Dementia (FTD) & MRI Brain Atrophy

Last Updated Date: November 19, 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 Frontotemporal Lobar Degeneration Neuroimaging Initiative*

Key Takeaways

• Quantitative brain atrophy measures from anatomical MRI scans can aid in diagnosing Frontotemporal Dementia variants.
• 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 FTD participants in the FTLDNI Study.
• In the FTD natural history cohort, we identified distinct spatial patterns of significant brain atrophy in the behavioral variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA) groups.
• Our approach requires substantially lower sample sizes to assess reduction of the observed atrophy compared to other quantitative image analysis tools.
• This work provides insights into regional brain atrophy and potentially aiding early readouts for disease-modifying treatments in FTD clinical trials.

FTD encompasses conditions with progressive neurodegeneration of frontal and temporal brain regions, producing distinct clinical subtypes characterized by unique anatomical impacts and symptoms. Behavioral variant FTD (bvFTD) involves personality and behavioral changes; non-fluent variant primary progressive aphasia (nfvPPA) affects speech resulting in motor speech impairment; and semantic variant primary progressive aphasia (svPPA) leads to progressive loss of word meaning among many other clinical symptoms. Early diagnosis and differentiation of these subtypes are essential for effective management and for optimizing clinical trial study designs.

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 FTD, as well as enable the rapid evaluation of novel therapeutics in clinical trials. Distinct patterns of significant brain atrophy were identified for bvFTD, nfvPPA, and svPPA groups. This data allows for estimates of sample sizes for assessing reduction of brain atrophy and can provide early insights for evaluating potential disease-modifying treatments.

The FTD data used for analysis was obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) study database. 59 PSP and 117 healthy control participants were included in the analysis. Subjects were evaluated by MRI at baseline, with follow-up assessment over the following 24 months. We performed voxel-wise gray matter density analysis, vertex-wise cortical thickness analysis, and regional volumetric analysis. We performed sample size calculations based on change over the 24 months for all measures.

Analysis of voxel-wise gray matter density and vertex-wise cortical thickness changes over a 6-24 month period revealed rapid, distinct atrophy patterns in each FTD variant. Regional volumetry assessments showed that significant atrophy was observed in the frontal and temporal cortex, hippocampus, and thalamus, alongside ventricular expansion. The svPPA variant exhibited the most accelerated progression, with hippocampal volume reductions reaching up to 15% over 24 months, compared to 6-7% reductions in bvFTD and nfvPPA, and minimal changes in healthy controls. Sample size calculations suggest that fewer than 50 subjects per arm could detect therapeutic effects within 6-18 months, especially in the hippocampus, temporal cortex, and amygdala across all FTD variants.

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 appear promising for evaluation of the efficacy of putative disease-modifying therapeutics for FTD in multi-center clinical trials.

Presentation Highlights

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