Table of Contents

Abstract

Presentation

01. Introduction 02. Regional Volumes Analysis Methods 03. Cortical Thickness Analysis Methods 04. TDP-43 Model 05. TDP-43 Model MR Images 06. TDP-43 Model MRI Analysis 07. Alpha-Synuclein Model 08. Synuclein Model MR Images 09. Synuclein Model MRI Analysis 10. Summary

Regional Volumes

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Brain volumes in various cortical and subcortical regions. The arrows show the progression of Off Dox mice that either continued off doxycycline until 6 weeks or were put back on doxycycline for 3 weeks. * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001

Cortical Thickness

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Cortical thickness measures in the motor and frontal cortical regions. The arrows show the progression of Off Dox mice that either continued off doxycycline until 6 weeks or were put back on doxycycline for 3 weeks. * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001

Cortical thickness map demonstrating the regions of cortical thinning in Low Dox compared to control mice. The colder colors (e.g. blue, purple) represent areas with significant atrophy. Note the high degree of specificity for the motor and frontal cortex at 8 weeks following disease initiation.

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We have been able to show highly significant brain atrophy in this model. In the Off Dox model, we see a rapidly progressive brain atrophy in the motor cortex volume and thickness, frontal cortex thickness, and hippocampal volume.

In contrast, in the slower Low Dox model, we see early changes in the cortical regions, without significant atrophy in the subcortical areas. This finding aligns well with the distribution of TDP-43 pathology.

Note that the cerebellum is largely spared from brain atrophy. Also, note that putting mice back on Dox effectively halts the neurodegeneration, thereby demonstrating the ability to achieve disease modification in this model.