Diffusion MRI & Frontotemporal Dementia (FTD) 

Last Updated Date: January 16, 2025

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 diffusivity and free water measures from diffusion MRI scans can aid in diagnosing frontotemporal dementia (FTD) variants. 
• We have used a fully-automated image processing "pipeline" purpose built for clinical trials for the computation of regional diffusivity and free water from diffusion MR images of FTD participants in the FTLDNI Study. 
• In the FTD natural history cohort, we identified distinct spatial patterns of significant structural differences in the behavioral variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA) and semantic variant primary progressive aphasia (svPPA) groups.  

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders characterized by progressive atrophy in the frontal and temporal lobes, leading to distinct behavioral, language, and executive dysfunctions. Using data from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI), we employed PIANO™, a fully automated diffusion MRI (dMRI) processing pipeline, to investigate brain microstructural changes in 106 participants. This cohort included 26 with behavioral variant FTD (bvFTD), 15 with non-fluent variant primary progressive aphasia (nfvPPA), 23 with semantic variant primary progressive aphasia (svPPA), and 42 healthy controls.

Diffusion MRI metrics, such as mean diffusivity (MD) for white matter and cortical regions and free water (FW) for subcortical regions, revealed distinct spatial patterns of microstructural change among FTD variants. bvFTD participants exhibited significant frontal and cingulate cortex alterations, reflecting their behavioral and executive impairments. svPPA participants demonstrated pronounced temporal lobe, amygdala, and associated white matter changes, consistent with their semantic deficits. nfvPPA participants displayed less localized microstructural alterations, with notable involvement of the corpus callosum. Over a 12-month period, voxelwise analysis showed significant increases in MD across all FTD variants, contrasting with minimal changes in healthy controls.

The analysis identified brain regions requiring the smallest sample sizes to detect therapeutic effects, emphasizing the svPPA group’s sensitivity to structural changes. These regions, including the temporal lobe in svPPA, the frontal lobe in bvFTD, and the corpus callosum in nfvPPA, demonstrated sample size requirements below 50 per arm to detect a 60% reduction in diffusion metric changes at 6 and 12 months.

These findings underscore the potential of diffusion MRI to enhance FTD clinical trials by enabling early detection of microstructural changes, tracking disease progression, and evaluating therapeutic efficacy. The PIANO™ pipeline’s automated image processing and robust regional sensitivity support its utility in refining trial design and advancing treatment strategies. This study provides critical insights into the spatial and temporal complexity of FTD variants, enabling disease-specific intervention targeting and minimizing trial participant numbers while maintaining statistical power. By integrating diffusion MRI metrics and leveraging both voxelwise and regional analyses, this research paves the way for more efficient and precise clinical trials in the context of FTD.

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.