Brain Atrophy Analysis in Mouse Models of Neurodegeneration

Last Updated Date: August 22, 2024

Authors: Kristina DeDuck, Ph.D., Robin Guay-Lord, Kung Yuan Lin, Simone P. Zehntner, Ph.D., Alex P. Zijdenbos, Ph.D., Elodie Brison, Ph.D., Barry J. Bedell, M.D., Ph.D.

Key Takeaways

• Quantitative brain atrophy measures based on anatomical MRI scans can overcome some of the limitations of conventional approaches.
• We have implemented fully-automated image processing "pipelines" for computation of regional neuroanatomical volumes and cortical thickness measures from high-resolution, structural MR images of mouse brain.
• In the TDP-43 ΔNLS mouse mouse model of ALS, we found statistically significant MRI brain atrophy with a specific spatial pattern, including motor and frontal cortical regions.
• In an α-synuclein preformed fibril (PFF) seeding mouse model of Parkinson's disease, we identified highly significant MRI brain atrophy in the ipsilateral anterior olfactory nucleus (PFF injection site), insula, piriform cortex, entorhinal cortex, and hippocampus.
• Our approach may provide sensitive and cost-effective in vivo measures of brain atrophy for the preclinical testing of the efficacy of disease-modifying therapeutics in animal models of ALS, Parkinson's disease, and other neurodegenerative diseases, such as Alzheimer's disease and tauopathies.

Brain atrophy is a hallmark of neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia, ALS, Parkinson's disease, multiple system atrophy, Huntington's disease, and multiple sclerosis. As such, the ability to prevent, slow, or halt brain atrophy is a key endpoint in many clinical trials of disease-modifying therapeutics. Magnetic resonance imaging (MRI) is the standard modality used to non-invasively evaluate brain atrophy in clinical trials. Imaging biomarkers, such as regional volumetric and cortical thickness measures, provide objective, quantitative indices of brain atrophy. A significant advantage of MRI is that it can also be applied to animal models of neurological diseases, thereby allowing for the use of "translational biomarkers" to help bridge the gap between preclinical and clinical studies.

The use of animal models that recapitulate the neurodegenerative aspects of human disease provides a powerful means of evaluating the ability of experimental therapeutic agents to modify brain atrophy during the preclinical phase of development. While a number of methods, including quantitative tissue-based measures and fluid biomarkers, can be used to assess neurodegeneration, MRI has the significant advantage of providing longitudinal, in vivo measures across all neuroanatomical regions.     

In this presentation, we describe our high-throughput, fully-automated methods to obtain clinically-relevant, translational measures of regional brain volumes and cortical thickness from in vivo MRI images acquired from rodent models of neurodegenerative diseases. We provide illustrative examples from mouse models of ALS and Parkinson's disease to demonstrate the utility of these measures in preclinical therapeutic efficacy studies.

In the TDP-43 ΔNLS mouse mouse model of ALS, including a slower progressing version implemented by our group, we identified a specific pattern of regional atrophy. Statistically significant cortical thinning was prominent in the  motor cortex and frontal cortex, which may represent specific vulnerabilities of the neuronal populations in these brain regions.

In an α-synuclein preformed fibril (PFF) seeding & spreading mouse model of Parkinson's disease (PD), wherein recombinant human PFFs are injected unilaterally into the anterior olfactory nucleus of transgenic (M83+/-) mice to generate a "limbic system model" of PD, we identified highly significant MRI brain volume reduction and cortical thinning in the ipsilateral AON, insula, piriform cortex, entorhinal cortex, and hippocampus, as well as the contralateral piriform cortex.

Structural MRI has several key advantages for the measurement of brain atrophy in preclinical studies of disease-modifying therapeutics for neurodegenerative diseases, including (a) non-invasive, in vivo measures without the confounds associated with tissue manipulation (e.g. extraction, fixation, processing); (b) opportunities for longitudinal measures in the same animal; (c) it is often the first biomarker to show disease progression (before conventional fluid & tissue markers); (d) one can obtain readouts from the in-life phase of a preclinical study that can serve as go/no-go decision points for additional post-mortem analyses; and (e) it allows for evaluation of the brain regions that are specifically affected in a particular disease model.

In vivo MRI brain atrophy measures can be complemented by fluid-based biomarkers, such as neurofilament light chain (NfL; NF-L) measures in the blood and CSF (also a clinically-translational biomarker), as well as by appropriate, quantitative immunohistochemistry (IHC) or multiplex immunofluorescence (IF) markers on post-mortem tissue sections. Through this "multi-modality" strategy, a high degree of sensitivity and specificity for analysis of neurodegeneration can be realized.

Presentation Highlights