MRI Brain Atrophy Analysis for Preclinical Drug Studies

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

Structural MRI has several key advantages for the measurement of brain atrophy in preclinical studies of disease-modifying therapeutics for neurodegenerative diseases:

Non-invasive, in vivo measures without confounds associated with tissue manipulation (e.g. extraction, fixation, processing)
Opportunity for longitudinal measures in the same animal
Often the first biomarker to show disease progression (before conventional fluid & tissue markers)
Can obtain readouts from the in-life phase that can serve as go/no-go decision points for additional analyses
Allows for evaluation of the brain regions that are specifically affected in a particular disease model

https://opt003stagmediafiles.blob.core.windows.net/image/b5c3eee2bd6049eb82817530e6ca5aea

In vivo MRI brain atrophy measures can be complemented by NfL measures in the plasma and CSF (also a clinically-translational biomarker), as well as by appropriate, quantitative immunohistochemistry or immunofluorescence markers on post-mortem tissue sections. Through this "multi-modality" strategy, a high degree of sensitivity and specificity can be realized.

--:--

In summary, MRI measures can be a cost-effective and time-efficient means of evaluating modulation of brain atrophy by potential disease-modifying therapeutic agents. We have demonstrated the high level of sensitivity of volumetric loss and cortical thinning in mouse models of ALS and Parkinson's disease that we routinely use in therapeutic efficacy studies.

MRI is widely used in CNS clinical trials, ranging from exploratory studies to large-scale, global, multicenter, Phase 3 studies. The ability to identify potential disease-modifying effects on MRI brain atrophy during preclinical studies presents a unique opportunity to de-risk future clinical trials and identify potential reliable biomarkers and endpoints.