Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.

Keywords:

• Amyotrophic lateral sclerosis
• diffusion tensor imaging
• neurite orientation dispersion and density imaging
• diffusion kurtosis imaging
• transgenic animals
• yellow fluorescence protein
• G93A-SOD1 mice
• neuronal degeneration

Acknowledgments

A portion of the work was performed in the Department of Anatomy and Cell Biology at the University of Illinois at Chicago (UIC), the Department of Pathology, Feinberg School of Medicine from Northwestern University and the Instituto de Fisiología Biologia Molecular y Neurociencias-IFIBYNE-CONICET, University of Buenos Aires, Argentina. MRI studies were conducted at the University of Florida in Gainesville, McKnight Brain Institute. We would like to acknowledge Dr. Gerardo Morfini at UIC for providing some chemicals and materials used in particular histological preparations.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This study was supported by the High Magnetic Field Laboratory (NHMFL) and Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) under Magnetic Laboratory Visiting Scientist Program [Award VSP #278] to RG. The McKnight Brain Institute at the National High Magnetic Field Laboratory’s AMRIS Facility is supported by National Science Foundation Cooperative Agreement No. DMR-1157490* and the State of Florida.

This study was supported by the High Magnetic Field Laboratory (NHMFL) and Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) under Magnetic Laboratory Visiting Scientist Program [Award VSP #278] to RG. The McKnight Brain Institute at the National High Magnetic Field Laboratory’s AMRIS Facility is supported by National Science Foundation (NSF) Cooperative Agreement No. DMR-1644779* and the State of Florida. National Institutes of Health (NIH) DK101675 to RS